A prominent risk factor for psychosis is its high heritability. This offers us a means to identify potential biomarkers of risk and resilience by focusing on people who are at familial high risk, but are currently free of both illness and medication. The genetic underpinnings of this risk allow us to gain a more mechanistic understanding, which may better guide therapeutic development and prevention strategies. Here, we summarize two prospective longitudinal familial high-risk studies: the Edinburgh High Risk Study of schizophrenia and the Bipolar Family Study. This work highlights the complex interactions between molecular mechanisms and environmental circumstances in the generation and perpetuation of psychosis.