This educational activity provides a comprehensive overview of treatment-resistant mood disorders, with a focus on major depressive disorder and bipolar disorder. Participants will review DSM-5-TR diagnostic criteria, differentiate between depressive and bipolar presentations, and explore common causes of treatment resistance, including pseudo-resistance. The activity emphasizes evidence-based treatment strategies, including pharmacologic optimization, augmentation approaches, and advanced interventions such as ketamine, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT). Practical considerations for evaluation and management in primary care and acute care settings are also discussed.