Bipolar disorder is a heritable psychiatric illness affecting approximately 1% of the population. The age of onset is generally in the late teenage years or early adulthood where there is a long delay from first symptoms to diagnosis of treatment. The aim is to demonstrate specific gene-environment, gene-gene interactions, or preceding clinical/biological changes that are more common in those who go on to manifest bipolar disorder in a high-risk population, providing the potential both to improve early identification and develop targeted early intervention programs. The ongoing Bipolar Disorder Molecular Genetics Pedigree Study has identified several hundred families with multiple cases of bipolar disorder. In collaboration with three US sites we are now proposing to assess and follow “at-risk” adolescents, ages 12 –30 years, in these and similar families. We will be recruiting a genetically−defined high−risk sample of “currently well” subjects that have a parent or sibling with bipolar I disorder or schizo−affective disorder (bipolar type). In the Sydney site, five hundred study subjects and one hundred controls will be studied. At baseline a battery of psychological tests (including structured interviews) will be conducted, blood samples will be drawn, and on a sub-sample of participants structural and functional magnetic resonance imaging (MRI) will be preformed. At 12 month intervals a sub-set of assessments that were given at baseline will also be conducted on at-risk participants. At least one parent of at-risk 12-18 year olds will complete questionnaires and a structured interview. The study will take 5-10 years to complete.