Aim: High-risk studies provide the opportunity to describe the early natural history of bipolar disorder (BD); however, findings have varied substantially. In this review, we compare different methods of ascertainment and assessment, and their impact on study findings. Methods: Through a literature search, we identified 11 high-risk studies meeting inclusion criteria for this review. Studies included were those that focused on lifetime psychopathology in the offspring as the main outcome and provided adequate information on the methods of family ascertainment, as well as on parent and offspring assessment. We compared and contrasted psychopathological outcomes in the offspring among the studies using different methods. Results: High-risk studies that identified affected parents through their involvement in neurobiological research and confirmed diagnosis in the parent and offspring through best estimate procedures tended to report lower rates of co-morbidity in the proband parent, lower rates of psychopathology in the non-proband parent, lower rates of attention deficit hyperactivity disorder and externalizing disorders, and older ages of onset of major mood disorders in the offspring compared with studies that identified affected parents through self-referral and confirmed diagnosis in the parent and offspring through structured research interviews. Studies that identified severely ill parents and used semi-structured assessments tended to have an intermediate position in terms of outcomes. Conclusions: This review indicates that different methods of family ascertainment and of assessment of parent and offspring impact the findings pertaining to lifetime psychopathology and clinical course of BD in high-risk studies. The implications of this finding for mapping the natural history of BD are discussed.