Medical comorbidity is commonly encountered in individuals with major depressive disorder (MDD) and bipolar disorder (BD). The presence of medical comorbidity has diagnostic, prognostic, treatment, and etiologic implications underscoring the importance of timely detection and treatment. A selective review of relevant articles and reviews published in English-language databases (1968 to April 2011) was conducted. Studies describing epidemiology, temporality of onset, treatment implications, and prognosis were selected for review. A growing body of evidence from epidemiologic, clinical, and biologic studies suggests that the relationship between medical illness and mood disorder is bidirectional in nature. It provides support for the multiplay of shared and specific etiologic factors interlinking these conditions. This article describes the complex interactions between medical illness and mood disorders and provides a meaningful approach to their comorbid clinical diagnosis and management.