Approximately 30% of people treated for a major depressive episode will not achieve remission after two or more treatment trials of first-line antidepressants and are considered to have treatment-resistant depression (TRD). Because the odds of remission decrease with every subsequent medication trial, it is important for clinicians to understand the characteristics and risk factors for TRD, subtypes of major depressive disorder that are more likely to be less responsive to first-line anti-depressants, and the available treatment options. In the current article, we review the approved treatments for TRD, including esketamine, and the evidence for psilocybin and pramipexole. Although limited in specificity, guidelines to help prescribers identify person-centered treatments for TRD are available. [Journal of Psychosocial Nursing and Mental Health Services, 59(9), 7-11.].