This paper addresses the issue of whether prevention research methods, particularly those involving randomized prevention trials, can be used to test theories concerning the etiology of psychopathology. Based on recent empirical and theoretical work in developmental psychopathology, three aspects of etiologic theory are discussed: risk and protective mechanisms, the integration of environmental and genetic factors, and patterns of developmental progression in psychopathology across the life span. It is suggested that integration of prevention trial methods with methods from passive correlational designs, behavioral genetics, and longitudinal studies allows for unique opportunities to test hypotheses about etiology. Empirical literature on the development and prevention of internalizing disorders, particularly depression, is presented to support this argument. Limitations of prevention trials for testing theory are also reviewed.