Depression or the presence of significant depressive symptoms remains common in patients with end-stage renal disease (ESRD). It is thought that 20–30% of ESRD patients have significant depressive symptoms, although there are issues surrounding the assessment of depression among patients with physical illness. Screening tools may be useful in this setting to identify patients with low affect, accompanied by formal diagnostic approaches which are important to consider following a positive screen. Recent evidence highlights the impact of depression upon mortality, and its association with non-adherence and immune parameters, work that supports past investigations. Further studies are required to better our understanding of the mechanisms behind depression in patients with ESRD identifying both psychological and clinical antecedents. A focus on the treatment of depression is now critical given the evidence that depression impacts upon outcome in ESRD. Antidepressants seem effective, but the prevalence of negative side effect profiles and drug–drug interactions suggest a role for psychotherapeutic approaches. Of these, cognitive behavioral therapy shows real promise.