The Research Domain Criteria (RDoC) reflects a paradigm shift in mental health research aimed at establishing a science of psychopathology that is grounded in neuroscience. In many ways, the RDoC approach to research has been utilized for decades by psychophysiologists who have leveraged a range of biological measures to study variability in psychological processes as a function of individual differences. We highlight the critical role of psychophysiology in the era of RDoC, and briefly review the 13 papers and commentary that form the current special issue.