Background:Depressive disorders are significantly more common in the medically ill compared to the general population. Depression is associated with worsening of physical symptoms, greater healthcare utilization and poorer treatment adherence. The present paper provides a critical review on the assessment and management of depression in the medically ill.Methods:Relevant articles pertaining to depression in the medically ill were identified, reviewed and synthesized qualitatively. A systematic review was not performed due to the large breadth of this topic, making a meaningful summary of all published and unpublished studies not feasible. Notable studies were reviewed and synthesized by a diverse set of experts to provide a balanced summary.Results:Depression is frequently under-recognized in medical settings. Differential diagnoses include delirium, personality disorders and depressive disorders secondary to substances, medications or another medical condition. Depressive symptoms in the context of an adjustment disorder should be initially managed by supportive psychological approaches. Once a mild to moderate major depressive episode is identified, a stepped care approach should be implemented, starting with general psychoeducation, psychosocial interventions and ongoing monitoring. For moderate to severe symptoms, or mild symptoms that are not responding to low-intensity interventions, the use of antidepressants or higher intensity psychotherapeutic interventions should be considered. Psychotherapeutic interventions have demonstrated benefits with small to moderate effect sizes. Antidepressant medications have also demonstrated benefits with moderate effect sizes; however, special caution is needed in evaluating side effects, drug–drug interactions as well as dose adjustments due to impairment in hepatic metabolism and/or renal clearance. Novel interventions for the treatment of depression and other illness-related psychological symptoms (e.g. death anxiety, loss of dignity) are under investigation.Limitations:Non-systematic review of the literature.Conclusion:Replicated evidence has demonstrated a bidirectional interaction between depression and medical illness. Screening and stepped care using pharmacological and non-pharmacological interventions is merited.