Major depressive disorder is a serious public health problem, representing a leading cause of worldwide disability, and a major contributor to suicide. While treatments exist to address this problem, they are not always efficacious, highlighting the need for more research to better understand the neural circuitry underlying depression and its treatment. In the past 2 decades, human neuroimaging research has made great strides in providing information about which neural circuits are implicated in depression. In this talk we will review some of the major contributions to this body of knowledge including research using structural neuroimaging, positron emission tomography, and functional magnetic resonance imaging. We will also discuss the smaller but emerging literature using these tools in the context of clinical trials to begin to understand predictors and mechanisms of treatment response in patients with depression. While there have been great strides forward in understanding the neural circuitry underlying depression, much work still remains before this knowledge can be applied in the clinic. Heterogeneity in the findings across studies may reflect heterogeneity of MDD itself, where individuals that fall under the same diagnosis may have different neural circuitry signatures. Advanced methods that are designed to better understand these differences across subjects could provide the traction needed to develop personalized treatment approaches.