The Health Disparities and Outcomes (HDO) model originally created to explain the complexity of obtaining healthcare in rural settings has been revised and updated using emerging theoretical models of adversity and inequity and two decades of empirical work by the authors. With a strong orientation to explaining population-based health inequities, the HDO is applied to individuals with Serious Mental Illness (SMI), to explain their high rates of morbidity and mortality compared to the general population. Individual-, community-, and system-level factors that reflect an understanding of life-long risk, accrued hazards associated with multiple and intersecting disadvantages, and difficulty obtaining healthcare that meets accepted standards are described. The revised HDO can be applied to populations with disproportionate health challenges to identify multi-level factors that affect illness trajectory and overall health outcomes.