A persistent challenge for the field of psychopathology has been how to best explain mental disorders and organize clinical symptoms into diagnoses. Meta-structural approaches have clarified fundamental problems and made substantial gains by using covariance structures to organize the nature of clinical symptom patterns. A remaining task is how to specify the connections between these patterns across behavioral, cognitive, and neural mechanisms. Together, meta-structural approaches and the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) offer a means to parse out these connections. I comment on the included articles in this special section on psychopathology meta-structure and argue that core dimensions of psychopathology identified with meta-structural approaches can advance the RDoC initiative and that the RDoC framework, in turn, can strengthen structural approaches by providing an organizational scaffold to elucidate the relations of behavioral, cognitive, and neural mechanisms and to relate them to dimensions of human suffering and dysfunction.