Now that the Enterprise crew is communicating regularly with Earth, Hoshi observes that Dr. Phlox is getting more letters from home than anyone else. Phlox has been corresponding with a human medical colleague named Dr. Lucas, who is now serving on Phlox's home planet Denobula. In his letters Phlox shares his observations of human behavior during their first deep space venture, and he mentions his growing relationship with Ensign Cutler, whom Phlox is mentoring to be a part-time medic and who he suspects is romantically interested in him. Phlox is called on to treat two alien astronauts rescued from a disabled pre-warp craft. The astronauts reveal they are from a planet called Valakis, and have been traveling in space for over a year searching for technology to develop a cure for an epidemic that is slowly killing their people. The Valakians appeal to Captain Archer to allow Phlox to help them, and without objection from T'Pol, Archer agrees and sets course for their world.

In a letter to Dr. Lucas, Phlox expresses the overwhelming feeling of taking responsibility for 50 million patients, but he is struck by the human desire to help others. Archer, Phlox, T'Pol and Hoshi visit a Valakian hospital and learn more about the epidemic and their unsuccessful attempts to treat it. They also learn there's a second humanoid species indigenous to the planet called the Menk who are less evolved than the Valakians but are very hard and loyal workers. The Menk have never contracted the disease, so Phlox begins his research with their immunity system, and he recruits Cutler to assist him. On a personal note, Phlox tells his pen pal that the affection Cutler is showing toward him is leaving him perplexed, and he goes so far as to ask T'Pol for advice.  Predictably, T'Pol thinks humans lack the emotional maturity for interspecies relationships. Meanwhile, Archer is getting pressured by Esaak, the director of the Valakian clinic, for a progress report, so he calls Phlox into his Ready Room. Phlox reveals that the illness is not viral or bacterial, but genetic — the proteins that bind the Valakian chromosomes are deteriorating and have been doing so for thousands of years, but the rate of mutation has accelerated over the last few generations, and Phlox projects that the Valakians will be extinct in less than two centuries. Archer wants to know if a cure is possible. Phlox believes that the Menk immunity could be the key, so he sets out to study them further.

With Hoshi and Cutler's assistance, Phlox visits a Menk village to run some tests and take blood samples. The relatively primitive Menk are cooperative, and one helper named Larr even begins to learn English just by listening to the visitors. Cutler and Hoshi start to suspect that the Menk are being exploited by the Valakians, even though the two species have developed a peaceful symbiotic relationship that seems to work. And after Larr organizes the blood samples in a sophisticated way, it becomes apparent that the Menk are more mentally evolved than they've been given credit for. Phlox tries to appease Cutler's concerns by pointing out that alien cultures have different ways. As an example Phlox addresses Cutler's apparent attraction to him, revealing that he already has three current wives back home, which is perfectly normal for his culture. Taken aback, Cutler admits her interest in him, but she doesn't want to be wife number four, only a friend. Meanwhile in the Valakian hospital, Archer visits one of the rescued astronauts, who insists that if Phlox can't cure them the Valakians need to acquire warp engines immediately to seek help elsewhere. This request puts Archer in a very uncomfortable position. Back on Enterprise, Archer relates the astronaut's request for warp drive to T'Pol, ironically beginning to understand how the Vulcans must have felt toward humans 90 years ago. Later in Sickbay, Phlox makes a very troubling discovery.

Meeting up in the Mess Hall, Archer asks Phlox if he's found a cure. The doctor says that even if one could be found, it may not be ethical to administer it, because such a cure would interfere with nature. Based on study of their genome, the Menk show evidence of an evolutionary awakening, and have the potential to become the dominant species on the planet, which won't happen as long as the Valakians are around. Archer counters that they have a moral obligation to help people who are suffering, despite theories of what may happen thousands of years hence. But then Phlox reveals that he already has the cure. Suddenly Archer is faced with an enormous dilemma. After spending the entire night reconsidering, he decides Phlox is right, and makes a decision that goes against all his principles. But he realizes that in the lack of some sort of directive telling him what he can and cannot do out in space, he has to remind himself that they're not out there to play God. He and Phlox deliver medicine to the Valakians to help ease their symptoms, perhaps long enough for them to find a cure on their own, but once again Archer has to reject their request for warp technology. Phlox closes his letter to Dr. Lucas saying that he's gained a new respect for Archer. But his heart is heavy so he takes Ensign Cutler up on her offer to be a friend.