As children, Maggie and Milo Dean seemed inseparable. But tragedy hit their family as teenagers when their father died, sending them on different paths, and ultimately leading to a decade-long estrangement. Now in their thirties, another set of near-tragedies brings them together. Melancholic Milo (Bill Hader), a frustrated actor with no prospects, decides to accept his sister’s offer to return to their hometown in bucolic upstate New York. However, he’s unaware that Maggie (Kristen Wiig) herself is barely holding it together, secretly unhappy despite her loving husband Lance (Luke Wilson).
At first, the bond between the twins is tentative: A surprise visit from their mother (Joanna Gleason), a new-age practitioner who refuses to recognize her children’s pain, only seems to amplify just how little Maggie and Milo have recovered from the events of their childhood. Secretly Maggie and Milo separately seek out relationships that are destined to go nowhere. Maggie enjoys the flirtatious attention of her hunky Australian SCUBA instructor (Boyd Holbrook) a little too much, sabotaging her interest in having a baby with Lance.
Meanwhile, Milo meets up with his first love, Rich (Ty Burrell). After their father’s death, Milo (as an older teenager) had an affair with Rich, his high-school English teacher – a scandal that drove brother and sister apart. At first, Rich is seemingly happy with a girlfriend and grown son and resents Milo’s sudden return. Desperate to get his former lover’s attention, Milo pretends to be successful and happy, which is enough to get Rich to consider rekindling their romance.
With painful wounds that only the other can understand, Milo and Maggie grow closer as they try to guide each other through this newest set of secrets. But as the hurt from the past catches up to the confusion in the present, their special bond is put to the test once again. They bring out not only the best in each other, but also the worst, and they are each desperate to avoid owning their own mistakes. Eventually Milo and Maggie grow to understand that living truthfully and sharing their lives with each other, pain and all, is the only way they can move forward and reclaim the happiness they once enjoyed together.