Depression is the most common psychological disorder in end-stage renal disease (ESRD) patients with a prevalence rate as high as 20% to 25% by some contemporary estimates. There are several studies linking depression with mortality in ESRD, making early diagnosis and treatment essential. The mechanisms linking depression with survival in ESRD patients are unclear but may be related to treatment compliance, improvement in nutritional parameters, increased perception of social support, and modulation of the immune system. Although the best methods for depression screening remain controversial, recent research has validated cutoff values for some of the more common depression screening questionnaires for evaluation in ESRD hemodialysis (HD) patients. A cutoff score of 14 to 16 for the Beck Depression Inventory is believed to have the most sensitivity and specificity at making the psychiatric diagnosis of depression in ESRD HD patients. There are limited data regarding the treatment of depression in ESRD patients. Selective serotonin reuptake inhibitors, at initial low starting doses, may be used in close consultation with mental health providers if no active contraindication to their use exists. Data on the mechanisms linking depression and mortality and the optimal treatment of depression in ESRD patients await the performance of randomized controlled clinical trials.