The U.S. National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) initiative offers a framework to facilitate integrative research to clarify core mechanisms of human mental distress and dysfunction. RDoC was developed to provide an alternative to research designed around clinical syndromes based on descriptive diagnosis. Rather than beginning with a syndrome and then working “down” to clarify mechanisms, the aim of RDoC is to guide research that begins with disruptions in neurobiological and behavioral mechanisms, and then works across systems to clarify connections among such disruptions and clinical symptoms. RDoC also departs from widely accepted categorical diagnoses instead advocating a dimensional account of clinically significant variance in disrupted mechanisms and symptoms. The need for RDoC stemmed from the realization that psychopathology research was not keeping pace with advances in clinical neuroscience and behavioral science, and the recognition that the cycle of scientific progress has been hampered by the instantiation of DSM diagnoses as the starting point of psychiatric research design. This chapter details the rationale and development of the RDoC and describes its structure. Some practical considerations and theoretical matters for implementing the RDoC alternative are considered.