Depression has been identified at the most prevalent psychologic problem in patients with ESRD treated with hemodialysis (HD). Depression has been associated with mortality in HD patients; however, the similarity of the symptoms of depressive disorders to those of uremia and the difficulties in measuring depression and dissociating psychologic from physical aspects of depression in such patients render these studies difficult to evaluate. Conflicting data regarding the effects of depression on survival in HD patients may be the result of using somatic symptoms in quantifying the extent of depression. In this review, studies regarding the diagnosis of depression in HD patients, the association of depression and survival in HD patients in light of recent work on factors related to the morbidity and mortality in the ESRD population, and aspects of therapy for depression in HD patients are considered. Specifically, depression may affect immunologic function, nutrition, and compliance factors that may affect the prescription and delivery of dialysis, which may, in turn, influence outcome. Alternatively, depression may be an independent factor in influencing survival. Cognitive depression measures may be more useful in predicting outcome in HD patients than standard measures used in nonmedically ill populations. Although there are few studies of the effect of treatment of depression on outcome in HD patients, it is reasonable to hypothesize that treatment of depressive disorders in HD patients might effect outcome. Further studies on the association of depression and its treatment and mortality in ESRD patients are warranted.