Most handgun projectiles have significantly lower energy than centerfire rifles. What they lack in power, they make up for it in light weight, small size, concealability and practicality. The lack of power they possess, and caliber/bullet effectiveness, are widely debated topics with growing experimental research among civilians, law enforcement, ammunition companies, and the military. Factors that can influence handgun effectiveness include handgun design, bullet types and bullet capabilities (e.g. wound mechanisms, penetration, velocity).
Most handgun projectiles wound primarily through the size of the hole they produce. This hole is known as a permanent cavity. For comparison, rifles wound through temporary cavitation as well as permanent cavitation. A temporary cavity is also known as a stretch cavity. This is because it acts to stretch the permanent cavity, increasing the wounding potential. The potential for wounding via temporary cavity depends on the elasticity of the tissue, bullet fragmentation, and the rate of energy transfer. Many handgun bullets do not create significant wounding via temporary cavitation, but the potential is there if the bullet fragments, strikes inelastic tissue (liver, spleen, kidneys, CNS), or if the bullet transfers over 500 ft·lbf (680 J) of energy per foot of penetration. These phenomena are unrelated to low-pressure cavitation in liquids.
There are many factors used to measure a handgun's effectiveness. One of them is penetration. The FBI's requirement for all service rounds is 12 inches (30 cm) penetration or greater in calibrated ballistic gelatin. This generally ensures a bullet will reach the vital organs from most angles. Penetration is arguably the most important factor in handgun wounding potential, because the vital areas must be destroyed or damaged to incapacitate.
Ballistic Pressure Wave/Hydrostatic Shock
There is a significant body of evidence that Hydrostatic shock (more precisely known as the ballistic pressure wave) can contribute to handgun bullet effectiveness.
Recent work published by scientists M Courtney and A Courtney provides compelling support for the role of a ballistic pressure wave in incapacitation and injury. This work builds upon the earlier works of Suneson et al. where the researchers implanted high-speed pressure transducers into the brain of pigs and demonstrated that a significant pressure wave reaches the brain of pigs shot in the thigh. These scientists observed neural damage in the brain caused by the distant effects of the ballistic pressure wave originating in the thigh.
The results of Suneson et al. were confirmed and expanded upon by a later experiment in dogs which "confirmed that distant effect exists in the central nervous system after a high-energy missile impact to an extremity. A high-frequency oscillating pressure wave with large amplitude and short duration was found in the brain after the extremity impact of a high-energy missile . . ." Wang et al. observed significant damage in both the hypothalamus and hippocampus regions of the brain due to remote effects of the ballistic pressure wave.
Damage to other nerves than those in the brain may lead to partial incapacitation (inability to walk or use the arms). 
Another factor is expansion and caliber. Many civilians and practically all law enforcement agencies use jacketed hollow point or some form of expanding ammunition. This increases the chance of a handgun bullet striking a vital organ, and increases blood loss. Because of this, two different calibers could theoretically produce almost identical incapacitation results, provided the two penetrate the same area, and the small caliber expands to the size of the larger.
It is generally agreed that most intermediate handgun calibers will perform similarly, since their wounding principles are the same. A list of many handgun calibers can be found at List of handgun cartridges.
The only scientifically proven and biologically possible way to guarantee instant incapacitation is through destruction of the central nervous system or brain. This will usually cease all motor-related and voluntary actions. If the central nervous system is not damaged or destroyed, there will be no immediate incapacitation. To allow room for error, since a central nervous system hit is very unlikely, most people use expanding ammunition. This will increase the odds of striking a part of the central nervous system, and cause faster blood loss.
For example, a popular caliber in the United States is the .45 ACP. It is the largest practical handgun caliber in use, featuring a bullet that is .452 inches in diameter. With well made expanding ammunition, a .452 bullet often expands to .70 caliber or larger. With a 9 mm Luger bullet, for example, its normal .355 diameter might be hoped to expand to .50 caliber or larger. This could give a preference for larger caliber bullets, as they do not rely on expansion as much as smaller caliber bullets do to provide incapacitation. However, multiple tests and actual data from shootings have not found this to be true.
The most popular round in the United States is the 9 mm Luger. The variety of handguns and ammunition available for this round is much higher than any other caliber. The amount of energy delivered to a body is dependent on both the weight of the bullet and its velocity as basic physics dictates. Thus NATO prefers the 9 mm Luger parabellum to a larger but slower round such as the .45 ACP
Bullet expansion in handguns is desirable not solely for incapacitation, but also so the bullet will not exit the target. An expanding bullet will stop in the target and "dump" all its energy there, rather than overpenetrating and possibly endangering people behind the target. Since all handgun rounds are marginal at best, the one with the most energy and which expends all that energy in a target is the one that is most effective.
- Jeremy J. Hollerman; Martin L. Fackler; Douglas M. Coldwell; Yoram Ben-Menachem (October 1990). "Gunshot Wounds: 1. Bullets, Ballistics, and Mechanisms of Injury" (PDF). American Journal of Roentgenology vol.155 no. 4: 685–690.
- Courtney M, Courtney A: Review of criticisms of ballistic pressure wave experiments, the Strasbourg goat tests, and the Marshall and Sanow data. http://arxiv.org/abs/physics/0701268 accessed 5/29/2007.
- Courtney M, Courtney A: Ballistic pressure wave contributions to rapid incapacitation in the Strasbourg goat tests. http://arxiv.org/abs/physics/0701267 accessed 5/29/2007.
- Courtney M, Courtney A: Relative incapacitation contributions of pressure wave and wound channel in the Marshall and Sanow data set. http://arxiv.org/abs/physics/0701266 accessed 5/29/2007.
- Courtney M, Courtney A: A method for testing handgun bullets in deer. http://arxiv.org/abs/physics/0702107 accessed 5/29/2007.
- Suneson A, Hansson HA, Seeman T: Pressure Wave Injuries to the Nervous System Caused by High Energy Missile Extremity Impact: Part I. Local and Distant Effects on the Peripheral Nervous System. A Light and Electron Microscopic Study on Pigs. The Journal of Trauma. 30(3):281-294; 1990.
- Suneson A, Hansson HA, Seeman T: Pressure Wave Injuries to the Nervous System Caused by High Energy Missile extremity Impact: Part II. Distant Effects on the Central Nervous System. A Light and Electron Microscopic Study on Pigs. The Journal of Trauma. 30(3):295-306; 1990.
- Wang Q, Wang Z, Zhu P, Jiang J: Alterations of the Myelin Basic Protein and Ultrastructure in the Limbic System and the Early Stage of Trauma-Related Stress Disorder in Dogs. The Journal of Trauma. 56(3):604-610; 2004.
- personal experience
- "Holster Effectiveness". Handgun Holsters. Retrieved 13 August 2015.