BD (bipolar disorder) is among the ten most significant causes of disability worldwide. Neuroscientists and clinicians have yet to meet the challenge of reducing this disability burden. The main obstacle to date has been our incomplete understanding of the pathophysiology of BD which thwarts primary prevention and early diagnosis and hinders effective treatment. There is a need to move beyond diagnostic approaches based purely on behavioural observation, as they lack reliability and biological validity. The present article reviews the evidence for cognitive, brain structural and functional correlates of genetic predisposition to BD and highlights biological markers of risk as well as factors that might protect against disease expression. It also outlines the rational and design of the Vulnerability to Bipolar Disorders Study (VIBES), which exemplifies a promising approach to delineating biological mechanisms mediating risk, resilience and disease expression in BD.