When Spock is stricken down by a disease fatal to Vulcans, the Enterprise is to meet a freighter with a load of drugs that provides the only cure, but Orion pirates attack the ship and Kirk must track down the Orions and the drug before it is too late.

The U.S.S. Enterprise hosts Commander Ari bn Bem, an arrogant member of a neutral race from the newly-contacted planet Pandro. However, Bem endangers all of their lives when he conducts a test of suitability upon Kirk and Spock during an exploratory mission. This occurs on a planet of primitive natives under the guardianship of a noncorporeal being.

After avoiding a Romulan ambush by three of their warships, the U.S.S. Enterprise enters a strange energy cloud. The gaseous cloud affects the ship's computer turning it insane. With the crew at the mercy of the Enterprise's computer, it indulges in a series of increasingly aggressive practical jokes.

Dr. McCoy is arrested and held responsible for causing a plague that ravaged the planet Dramia Two, where he performed a mass-innoculation 19 years earlier.

Backtracking a mysterious alien probe, the U.S.S. Enterprise encounters a ship in the shape of a giant feathered serpent, which turns out to be Kukulkan, a god of ancient Mayan-Aztec legend. Its captain, Kukulkan, is actually a very long-lived benevolent entity who wants the humans to worship him just as the Mayans and Aztecs did. He insists on putting Kirk and others through a test to determine if they have grown sufficiently to receive his wisdom.

With Commodore Robert April (the first commander of the Enterprise) on board, Kirk pursues a ship plunging into a supernova, and enters a universe where time runs backwards.