When two or more adequate antidepressant trials fail, the problem isn’t just “more of the same”—it’s a different disease state with distinct biology and care needs. Treatment-Resistant Depression reframes evaluation and treatment to uncover reversible drivers, stratify biology, and build multi-modal plans. We start with verification: confirm diagnosis (unipolar vs. bipolar), episode course, dose/duration/adherence, and hidden confounders—sleep apnea, circadian disruption, chronic pain, substance use, thyroid and inflammatory disorders, and meds that worsen mood. Phenotyping matters: anxious vs. anergic TRD, mixed features, melancholic vs. atypical patterns, and cognitive burden. We stage options by mechanism and practicality: augmentation (lithium, atypical antipsychotics, thyroid), switches (SNRIs, MAOIs in expert hands), and rapid-acting pathways under protocolized settings. Psychotherapy is re-matched to phenotype—CBT for cognitive distortions, BA for anergy, CT-SAD elements for social fear, trauma-focused work where indicated—and embedded with measurement so gains are visible. Sleep and circadian repair (CBT-I, anchor wake times, light/melatonin timing) often unlock stalled cases. For neurostimulation, we compare TMS variants and maintenance strategies; for ECT we outline when psychosis, catatonia, or imminent risk demand speed; and we integrate relapse-prevention scripts into discharge. Implementation details carry outcomes: medication stewardship (side-effect checks, metabolic monitoring), safety nets for suicidality, and choreography of care transitions. Equity includes transport, cost, language, and digital access to keep complex plans feasible. With disciplined troubleshooting and layered mechanisms, Treatment-Resistant Depression, the shared experience at a TRD conference, and decision anchors like augmentation strategies turn “failed trials” into forward motion.