Since the inception of Brain, Behavior and Immunity twenty years ago, many exciting developments have occurred regarding the relationship between depression and the immune system. These developments have increasingly put the field of psychoneuroimmunology into a clinical context with important translational implications. Initial studies focused on the impact of depression on relatively narrowly defined immunologic endpoints, which ultimately found their relevance in studies examining the effect of depression on immunologically-based diseases including infectious illnesses, autoimmune disorders, and cancer as well as more recently cardiovascular disease. Mechanistic studies have also greatly contributed to an understanding of those facets of depression, which might mediate these effects. More recently, the reciprocal influences of the immune system on the brain and behavior including depression have taken center stage. Increasing data now indicate that activated inflammatory processes can influence multiple aspects of CNS function including neurotransmitter metabolism, neuroendocrine function, and information processing leading to behavioral changes in humans that bespeak depression. These latter developments have intrigued scientists investigating the pathophysiology of depression and warrant consideration as some of the most exciting new developments in psychiatry in the past 20 years. What the future holds is a world of promise as multiple translational targets derived from the cytokine model of depression work their way into the clinical arena as drug targets for further development. Moreover, the work has served to instantiate brain-immune interactions as an essential component in psychiatric and medical co-morbidities and their impact on health and illness.