There is mounting evidence for a close relationship between obesity and depression. Depression is frequent in obese subjects and, in turn, obesity is associated with a greater risk of depression. Moreover, recent data suggest a role for obesity in treatment-resistant depression. While the association is bidirectional, the paths and mechanisms by which obesity can lead to depression appear to be particularly relevant to biological psychiatry, as they can provide new information on the pathophysiology and treatment of mood disorders. This chapter will review those pathophysiological pathways and processes that are shared by obesity and depression and that are likely to underlie the intricate relationship between the two disorders. Their potential translational implications and relevance to the development of personalized strategies for the treatment and management of depression will be further discussed.