As a commentary for the special section on Reconceptualizing the Classification of Mental Disorders, this article begins with a description of the impetus for the U.S. National Institute of Mental Health's (NIMH) Research Domain Criteria (RDoC) initiative and provides an update of progress on that initiative to date. The commentary then engages the articles in this special section, beginning with a response to Berenbaum's concern that the RDoC approach to sorting constructs across multiple units of analysis espouses a de facto biological fundamentalism. This leads us to delineate the relationship between RDoC and the NIMH priorities relevant to this initiative. The commentary then considers how Patrick's iterative "construct-network" method can be applied to RDoC construct validation, highlighting several aspects that are particularly useful. One aspect of this work involves determining subject inclusion and exclusion criteria that provide an appropriate range of variance. Finally, this commentary considers the Bilder group's article, explicating the ways in which multilevel models can foster development of hypotheses and informatics approaches needed for further RDoC progress.