The last 20 years of clinical neuroscience research has witnessed a fundamental shift in the conceptualization of neuropsychiatric disorders, with the dominant psychological and neurochemical theories of the past now complemented by a growing emphasis on developmental, genetic, molecular, and anatomically based, system-level models. Facilitating this evolving paradigm shift has been the growing contribution of in vivo functional and structural brain imaging techniques that provide an integrative platform to characterize brain circuit dysfunction underlying specific syndromes as well as changes associated with their successful treatment. The impact of this approach is demonstrated by the recent testing of a targeted neuromodulation strategy, deep brain stimulation (DBS), for treatment-resistant major depression. This intervention leverages the system-level models and targeted stimulation techniques pioneered for the treatment of Parkinson's disease to this and potentially other intractable neuropsychiatric disorders. The theoretical and data-driven foundation for one such imaging-derived network illness model and the initial proof-of-principle testing of subcallosal cingulate white matter DBS for depression is used to illustrate the potential of this evolving treatment strategy.