A high degree of comorbidity exists between depression and a constellation of other illnesses. The comorbidity between major depressive disorder (MDD) and several neurodegenerative disorders, the aftermath of stroke, and heart disease, might involve several common mechanisms This chapter provides a broad overview of some of the neurochemical processes that have been implicated in major MDD, including the classical neurotransmitters, as well as more recent conceptualizations concerning mechanisms that might underlie this illness. The processes related to MDD are explored from multiple perspectives, making it clear that several organismic variables and experiential factors contribute to the provocation and the maintenance of this illness, as well as relapse/recurrence that frequently occurs following successful treatment. Just as the symptoms of depression, as well as the etiological processes associated with MDD vary across individuals, the disorder appears to be biochemically heterogeneous. Multiple neurochemical processes may additively or interactively subserve MDD, and the constellation of factors that are related to depression in one individual may differ from those associated with depression in a second.