Depression has been identified as a complicating comorbid diagnosis in a variety of medical conditions, including end-stage renal disease (ESRD). Despite this, the psychological health of hemodialysis patients is understudied. The purpose of this paper is to review the research and issues involved in the assessment of depression and its sequelae in ESRD. Accurate estimation of the prevalence of depression in the ESRD population has been difficult due to the use of different definitions of depression and varied assessment techniques, the overlap of depressive symptomatology with symptoms of uremia, and the confounding effects of medications. We suggest that depressive affect is a more important construct to study than diagnosis of depression syndromes per se in patients with chronic kidney disease. The Beck Depression Inventory is a reasonable measure of depressive affect in the ESRD population, if a higher than usual cutoff score is used or if its somatic components are omitted. Several pathways link depression and ESRD, and are probably bidirectional. As such, treatment of depressive affect could impact medical as well as psychological outcomes. The need for treatment intervention trials is great. Limited evidence regarding the safety and efficacy of treatment of hemodialysis patients with selective serotonin reuptake inhibitors is available, and cognitive behavioral therapy holds promise as an intervention for depression in this complex medical population.