Depression has been thought to be the most common psychiatric abnormality in hemodialysis (HD) patients. There are few data using psychiatric diagnostic criteria and a lack of large, well-designed epidemiologic research studies in patients with end-stage renal disease (ESRD) that can render definitive results on this topic. The prevalence of major depression or a defined psychiatric illness in ESRD patients is unknown, but is probably between 5% and 10%. The prevalence of increased levels of depressive affect is greater. Estimates of the prevalence will vary according to the screening techniques used. Depression could affect medical outcomes in ESRD patients through several mechanisms. Correlational analyses suggest stressors and protective factors play roles in mediating the level of depressive affect and associated outcomes. Although early studies suggested a deleterious effect of depression on survival in ESRD patients, more recent studies had failed to confirm such findings. The use of longitudinal analyses and larger samples has confirmed an association of depressive affect and morbidity and mortality in more contemporary ESRD populations. The importance of depressive affect compared with the presence of a defined psychiatric syndrome in mediating clinically important outcomes in patients with chronic kidney disease has not been determined. Studies of interventions designed to reduce levels of depressive affect in ESRD patients are urgently needed.