Just like Houses of the Molé, Rio Grande Blood contains very political lyrics, making frequent allusions to the George W. Bush administration. The second track makes an explicit reference to Bush as Señor Peligro, which translates to "Mr. Danger" in Spanish. Some of the issues raised include the then-current Iraq War, U.S. immigration policy and U.S. military policy (particularly the US Marine Corps in the song "Gangreen"). The Halliburton corporation is also quoted and linked to the Bush administration.
A remix of the song "The Great Satan" from Rantology appears on this album. Along with "LiesLiesLies", "The Great Satan" was also nominated for a Grammy.
Samples of genuine Bush soundbites are cut-and-pasted together at various points to satirical effect: for example, the title track begins with Bush stating "I have adopted sophisticated terrorist tactics and I'm a dangerous, dangerous man with dangerous, dangerous weapons."
The album was re-released in remixed form as Rio Grande Dub on July 10, 2007.