<p>Stagnation in the development of novel strategies for the management of major depression and other neuropsychiatric disorders has left many patients with unmet treatment needs. This state of affairs has encouraged critical appraisal of the very relationship between preclinical findings and their clinical applications in psychiatric practice. One consequence of such reflection has been a growing emphasis on <i>reverse translation</i> in preclinical research. Traditional preclinical approaches with laboratory animals have most often used a forward translational approach designed to identify classes of organized animal behavior that serve to predict outcomes in humans. On the other hand, reverse translational approaches identify patterns of human behavior revealed by task performance to develop assays with maximal formal similarity in laboratory animals. Presumably, such correspondence will evoke functionally similar behavioral outcomes across species, allowing for rigorous assessment of innovative, sometimes invasive, behavioral and pharmacological treatment strategies impossible to examine in human subjects without substantial preclinical evidence of safety and efficacy. Following validation and optimization, a reverse translational framework can be used for coordinated bidirectional pursuits across species to accelerate the drug discovery process. To aid appraisals of emerging reverse translational techniques, the present review outlines five considerations based on their longstanding association with rigorous assessments in behavioral science and informed by behaviorist traditions. Emphases on behavior, pharmacology, environmental determinants, levels of analysis, and cross-species continuity are discussed, with an emphasis on the Research Domain Criteria (RDoC) framework to advance innovative therapeutic strategies for treatment-resistant neuropsychiatric illness.</p>