During the same 20 years that antidepressant therapy has minimally advanced, our understanding of the brain has exploded, especially because of increasing knowledge of the functional neuroanatomic, molecular, and genetic control of emotional network function and the neural basis of affective illness (see, for example, references 5–7). What has lagged is applying this new information in order to identify novel interventions for depression. One alternative goal has been to try to personalize treatment by identifying subpopulations of depressed patients who respond differently to different treatments; however, attempts to meet this goal are limited by a collection of medications that essentially share the same mechanism of action (i.e., SSRIs). Recent innovations using neuromodulatory therapies (e.g., repetitive transcranial magnetic stimulation , ketamine administration , or circadian rhythm regulation ) are beginning to challenge standard models of depression, partly on the basis of advances in neuroscience, thereby providing alternatives to permit personalization and, in the process, refine different neurophysiological models for depressive disorders. A paradigm shift in the treatment of depression is overdue, and translational neuroscience, like that presented in this issue (3), presents a step toward that end. Perhaps this study will inspire others to use a similar translational approach leading to a significant advance in how we manage folks with major depression.