Set in the 22nd century, the series follows the adventures of the first Starfleet starship, Enterprise, registration NX-01. This episode sees alien entities test the Enterprise crew by observing their reactions to a deadly silicon-based infection. Actual first contact with these aliens – the Organians – would occur about a century later, during the events of the original series episode "Errand of Mercy".
As Lieutenant Reed and Ensign Mayweather play chess, it quickly becomes apparent that they are serving as hosts to non-corporeal aliens. Returning from an away mission, Commander Tucker and Ensign Sato soon exhibit symptoms of a strange disease. Upon examination by Doctor Phlox, it is found to be a highly contagious silicon-based virus, and Captain Archer explains that Commander T'Pol and Phlox are seeking a cure. To pass the time, while isolated in Decontamination, the two try to learn more about each other.
The aliens take a keen interest examining the human response to this crisis, and compare notes to previous reactions by Klingons and Cardassians. It is also clear they are members of an advanced species looking to make "first contact". So far, based on 10,000 years of observations, no species has yet been deemed ready. Seeking a different view of the crew, they temporarily shift to the bodies of Phlox, T'Pol, and Archer, and a difference in opinion between the two aliens starts to form: one seems determined to maintain their non-interference protocol, while the other feels the protocol is outdated and unnecessary.
With time running out, Phlox and T'Pol find a way to disrupt the virus using deadly levels of radiation. Archer and Phlox escort Tucker and Sato to Sickbay for treatment. Sato soon goes into cardiac-arrest, and Archer removes his EV gloves and helmet to assist her, but she cannot be resuscitated. They then administer a dose of radiation to Tucker, but that too is ineffective. Phlox then leaves to resume work from the Bridge. Suddenly, Tucker and Sato reanimate as the aliens explain the situation to a surprised Archer, who then makes an impassioned speech on behalf of his crew. The aliens change their protocols, wiping the encounter from memory, but also neutralizing the virus. Archer orders a warning beacon to be placed above the planet, as the aliens leave to begin planning a future first contact with more advanced Humans.