The series follows siblings Kevin, Kate, and Randall (known as the "Big Three") as their lives intertwine, and their parents Jack and Rebecca Pearson. It is shown in both present day and in flashbacks. 

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Kevin and Kate are the two surviving members of a triplet pregnancy, conceived after Super Bowl XIV at "Froggy's" in Pittsburgh. Their due date is October 12, 1980, but they are born six weeks early on August 31 (Jack's birthday); their biological brother is stillborn. After losing their third baby, Jack and Rebecca decide to adopt Randall, a black child born the same day and brought to the same hospital after his biological father abandons him at a fire station.

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Episodes weave through the stories of the past and present of the characters, with most scenes taking place in four periods: c.1980-1981, c.1988-1990, c.1995-1998, and the present day (2016-2018). Most flashback scenes occur in Pittsburgh, where the "Big Three" are born and raised. Current scenes are typically split among Los Angeles, New Jersey, and New York City. In each episode, most flashback scenes, relate to current scenes, shows Jack, who dies when the "Big Three" are 17-and Rebecca when they are either babies, ages 8-10, or ages 15-17.