After an opening scene that depicted a slave ship getting sunk because those on it were infected with smallpox, we see the children of a new family dying: the man and woman were recently married and each have a child. But when the woman's daughter comes up with a jar from the wreckage of the aforementioned ship, and then it breaks in her hand, the family is sent to Princeton Plainsboro.
She's developing the kinds of sores that resemble smallpox, which forces House and his team to call CDC. This organization locks down the hospital and quarantines the family. As they do, House continues to work on the case by trying to translate the captain's log from 1793. He uses an online Dutch sex operator to help. Funny stuff.
There's a lot of back and forth, as usual, made extra awkward by the fact that Cuddy remains angry as House for lying to her last week. But he eventually concludes that the father, who is also showing signs, does NOT have smallpox. As a result, he actually enters that man's restricted area and tries to give him a cure for lung disease.
But the man does not respond and now there's a fear that he really does have smallpox, and House is in serious trouble. Fortunately, Masters conducts more research and thinks the disease is a different kind of pox. She urges House to search the man's body for a certain type of scar (he's passed away). House does so, finds the scarring and is relieved that this kind of pox has a cure. The girl's life is also saved, but House is sad to learn at the end that Cuddy is still mad at him.
Elsewhere, after dealing with a cancer patient for the episode, Wilson suggests to Sam that they try to have a baby.