Major depressive disorder (MDD) is a complex disease and is one of the leading causes of disability in our society. The provoking factors are multiple; acute and chronic psychological stress, severe early trauma experiences, somatic disease, and genetic factors all play a role. This review focuses on hyperdrive of corticotropin-releasing hormone (CRH) as the fundamental neurobiological correlate of MDD. CRH plays a key role in the adaptation to acute stress, but chronic CRH hyperdrive leads to a number of disadvantageous emotional and somatic effects. The evidence that the HPA axis is hyperactive in MDD, probably as a result of a primary hyperdrive of CRH, comes from multiple sources: biochemical studies, functional HPA axis tests, neuroimaging and postmortem studies, and clinical trials with HPA axis-related compounds. The liability to develop CRH hyperdrive is probably partly genetic. For a number of relevant genes, transgenic animal studies and human association studies indicate a role in HPA axis regulation and the liability to develop CRH hyperdrive. These data are reviewed. Finally, early adverse experience can produce a lasting effect on HPA axis regulation as well, probably leading to a lifelong tendency to develop chronic CRH hyperdrive in response to stress. This has been shown in a number of animal studies, and recently some data in humans with early trauma have become available as well. Taken together, these findings allow formulating an integrative hypothesis, with CRH hyperdrive at the core, bridging the old dichotomy between biology and psychology in our thinking about MDD.