The executive Beth Emhoff returns from a business trip to Hong Kong with a stop over at the Chicago airport, where she has sex with her former lover. Beth feels ill but she believes that the problem is jet leg. She travels back home to Minneapolis and spreads the virus to her son Clark and her husband Mitch. When Beth and Clark die, Mitch goes in quarantine where the doctors realize that he is immune to the mysterious virus. Meanwhile in Hong Kong, London and in a small province, people have the same disease. The American CDC and the World Health Organization give their best effort researching the virus that is spreading in a geometric progression. The outbreak is threatening the worldwide population of annihilation, unless a vaccine is well-succeeded. The scientists begin a fight against time.

In 1972, a scale of measurement was established for alien encounters. When a UFO is sighted, it is called an encounter of the first kind. When evidence is collected, it is known as an encounter of the second kind. When contact is made with extraterrestrials, it is the third kind. The next level, abduction, is the fourth kind. Modern-day, Alaska, where-mysteriously since the 1960s-a disproportionate number of the population has been reported missing every year. Despite multiple FBI investigations of the region, the truth has never been discovered. Here in this remote region, psychologist Dr. Abigail Tyler began videotaping sessions with traumatized patients and unwittingly discovered some of the most disturbing evidence of alien abduction ever documented. The Fourth Kind exposes the terrified revelations of multiple witnesses. Their accounts of being visited by alien figures all share disturbingly identical details, the validity of which is investigated throughout the film.

Susan Jordan, a local novelty shop owner and terminally ill woman, has been given little more than six months to live. As her body destroys itself and her time runs out, she searches desperately for a way to extend her life. When the means to her survival fall into her lap, in the form of a mysterious vial, she blindly administers the treatment on herself. Her life is saved but she begins to be plagued by violent flashbacks and fits of rage. She discovers that Randolph Kaminsky, a doctor in the 1930's, created a drug which would eliminate incurable diseases and prolong life but only when combined with the breath of a dying person. Using himself and violent death-row prisoners as guinea pigs, he discovered that the formula had a drastic side effect: those who inhaled the breath of the prisoners would take on their memories...and their violent personalities. Now, in a race against time, Susan must find a way to reverse the effects before the drug is released into the general population and she commits an act that cannot be undone...murder.