Abstract Background Numerous studies have observed that offspring of bipolar parents manifest a broad spectrum of psychiatric disorders. We tested the hypothesis that in high risk offspring, bipolar disorder evolves in a predictable clinical sequence from non-specific (non-mood) to specific (mood) psychopathology. Methods Offspring from well-characterized families with one bipolar parent (high risk) or two well parents (controls) were assessed annually or at anytime symptoms developed using KSADS-PL interviews for up to 15 years. DSM-IV diagnoses were made on blind consensus review using all available clinical material. We compared the age-adjusted risks of lifetime psychopathology between high risk and control subjects and assessed the conditional probability of developing a mood disorder given a history of non-mood disorders. In subjects meeting full DSM-IV criteria for bipolar disorder, we assessed the sequence of psychopathology against a clinical staging model. Results High risk offspring manifest higher rates of anxiety and sleep disorders, as well as major mood and substance use disorders compared to controls. Antecedent anxiety increased the age-adjusted risk of mood disorder from 40 to 85% (hazard ratio of 2.6). High risk subjects who developed a mood disorder had an increased risk of a substance use disorder (hazard ratio of 2.4), typically meeting diagnostic criteria during or after the first major mood episode. The evolution of psychopathology leading to bipolar disorder generally followed the proposed sequence, although not all subjects manifest all stages. Limitations Larger numbers of high risk offspring prospectively assessed over the risk period would allow confirmation of these preliminary findings. Conclusions Clinical staging may be a useful approach to refine the early diagnosis and facilitate research into the evolution of bipolar disorder in those at familial risk.