Melancholia is typified by features of psychomotor slowing, anxiety, appetite loss and sleep changes. It is usually observed in 20-30% of individuals meeting diagnostic criteria for major depressive disorder (MDD). There is currently no agreement on whether melancholic MDD represents a distinct entity defined by neurobiological as well as clinical features or, rather, a specifier for MDD. This situation is reflected in the revisions to DSM, including in the DSM-5 due for release in 2013. With this context in mind, the authors review the origins of the construct of melancholia in MDD, its theoretical grounding and the defining characteristics that arose from this research. The authors then outline the state of knowledge on the neurobiology of melancholia. This second aspect is illustrative of the National Institutes of Mental Health's research domain criteria initiative, which offers a framework for redefining constructs along neurobiological dimensions. The authors also consider the outlook for identifying a useful biosignature of melancholia.