Depression disproportionately affects patients with kidney disease, including those with nondialysis chronic kidney disease, end-stage kidney disease requiring dialysis, and kidney transplant recipients. Patients across the spectrum of kidney disease should be screened for depression every 6 to 12 months using self-report questionnaires, followed by an interview with a clinician to confirm the presence of sadness or anhedonia when depressive symptoms are identified. Pharmacologic treatment with selective serotonin reuptake inhibitors has not consistently shown benefit compared with placebo and may be associated with serious adverse outcomes including cardiovascular events, bleeding, and fractures. However, based on the availability of alternative therapies, a watchful trial with close monitoring for therapeutic and adverse effects is reasonable. Several clinical trials have suggested that cognitive behavioral therapy and physical activity improve depressive symptoms when compared with a control group. Given the low risk associated with these therapies, they should be recommended to patients who have access and are amenable to such interventions. Future trials are needed to study therapeutic options for depression in nondialysis chronic kidney disease, peritoneal dialysis, or kidney transplant recipients, as well as alternative pharmacologic therapy and combination therapies. Given improvement in depressive symptoms with placebo in existing trials, inclusion of a control group is paramount.