The authors developed a methodological basis for investigating how risk factors work together. Better methods are needed for understanding the etiology of disorders, such as psychiatric syndromes, that presumably are the result of complex causal chains. Approaches from psychology, epidemiology, clinical trials, and basic sciences were synthesized. The authors define conceptually and operationally five different clinically important ways in which two risk factors may work together to influence an outcome: as proxy, overlapping, and independent risk factors and as mediators and moderators. Classifying putative risk factors into these qualitatively different types can help identify high-risk individuals in need of preventive interventions and can help inform the content of such interventions. These methods may also help bridge the gaps between theory, the basic and clinical sciences, and clinical and policy applications and thus aid the search for early diagnoses and for highly effective preventive and treatment interventions.