Major depressive disorder (MDD) is a highly prevalent disease, frequently characterized by recurrent or chronic course, and by comorbidity with other medical illnesses. The lifetime prevalence of MDD ranges up to 17% in the general population, and it almost doubles in patients with diabetes (9-27%), stroke (22-50%), or cancer (18-39%). Moreover, MDD worsens the prognosis, quality of life, and treatment compliance of patients with comorbid medical illnesses. Similar to what is observed with other comorbid illnesses, MDD worsens the outcome of kidney disease patients by increasing both morbidity and mortality. Treatment of depressive symptoms in renal failure patients increases medication acceptability and therefore potentially improves the overall patient outcome. The issue of the safety of antidepressant treatment in subjects with renal failure is frequently counterbalanced by the risks associated with depression comorbidity, provided that antidepressants with a low volume of distribution and low protein binding are prescribed, and most important, at low initial doses. Screening for CYP isoenzyme interactions with current medications is also recommended before starting antidepressant treatment.