The Research Domain Criteria (RDoC) initiative promoted by the National Institute of Mental Health emphasizes a dimensional approach to psychopathology that is agnostic to DSM diagnosis. The RDoC project offers exciting possibilities for advancing research aimed at preventing psychopathology. However, prevention has historically been defined using diagnostic status, requiring the field to redefine what constitutes prevention using an RDoC approach. This article outlines new criteria for prevention in the RDoC context and provides guidance for implementing these criteria. We also describe the role of prevention-mechanism trials that examine whether preventive interventions change proximal etiological mechanisms known to be associated with psychopathology. We hope that these modified criteria and recommendations will stimulate new possibilities for prevention research that will advance the field.