Assessing the consequences of specific diseases on global, national, and individual levels is complex. The Global Burden of Disease Study was launched in 1992 to develop objective measures of the burden of disease. Two measures have become widely accepted: disability-adjusted life-years (DALYs) assesses years of life lost due to a disease plus years lived with the disability due to that disease, and years lived with disability (YLDs) is a related measure with greater relevance for diseases that do not routinely produce earlier mortality. When DALYs and YLDs were compared world-wide for 100 disorders, they revealed a huge burden of disease for depression. Indeed, the findings were startling. Neuropsychiatric conditions are by far the world's leader in YLDs, accounting for almost 30%. Unipolar major depressive disorder alone accounted for 11% of global YLDs. The disability of major depressive disorder produces its greatest burden upon women and starts early in life. No separate disability assessments have been compiled for treatment-resistant depression, but of individuals with major depressive disorder, the most severely disabled are those with treatment-resistant depression. The contributions to the morbidity associated with major depressive disorder and treatment-resistant depression include widespread prevalence; relatively early symptom onset; severe underdiagnosis and undertreatment; genetic vulnerabilities and precipitation or accentuation by relatively unavoidable stressors; a longitudinal pattern of frequent recurrences with increasing frequency, severity, and consequences unless treated with maintenance strategies; inadequate prioritization of recurrence prevention among clinicians; and possible suppression of brain neurogenesis, neuronal atrophy, cell death, hippocampal dysfunction, and magnetic resonance imaging changes for those with chronic treatment-resistant depression. Since the patterns of recurrences, cycle acceleration, and increasing severity of treatment-resistant depression are key reasons for its high burden, reducing the burden requires an entire paradigm shift, including emphasis on the prevention of recurrences. Only then will this prevalent, disabling yet treatable disorder lose its ignominious status as a world leader in disease burden.