Adolescent offspring of parents with bipolar disorder (BD) are at high risk to develop BD and other psychopathology, yet how this risk continues into middle adulthood remains unknown. This study aimed to determine the window of risk for BD and other psychopathology in offspring of parents with BD followed from adolescence into adulthood. This study reported on the 22-year follow-up assessment of the Dutch Bipolar Offspring Study, a fixed cohort study of 140 participants established in 1997. Offspring (n= 100; mean [SD] age= 38.28 [2.74] years) of parents with bipolar I disorder or bipolar II disorder were assessed at baseline and 1-, 5-, 12-, and 22-year follow-up. No new BD onsets occurred since the 12-year follow-up (lifetime prevalence= 11%-13%; bipolar I disorder= 4%; bipolar II disorder= 7%). Lifetime prevalence of any mood disorder was 65%; for major depressive disorder, prevalence was 36%; and for recurrent mood episodes, prevalence was 37%. Prevalence of major depressive disorder more than doubled in the past decade. Point prevalence of any psychopathology peaked between 20 and 25 years (38%-46%), subsiding to 29% to 35% per year after age 30. Overall, 71% of offspring contacted mental health services since the last assessment. The risk for homotypic transmission of BD in offspring of parents with BD is highest during adolescence. The heterotypic risk for mood disorder onset and recurrences continues over the life course. Severe mood disorders are often preceded by milder psychopathology, emphasizing the need for early identification and interventions. This study allows for better understanding of the onset and course of mood disorders and specific windows of risk in a familial high-risk population.