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During recent years, the need to consider effective and innovative ways to prevent and end homelessness among individuals with serious mental illness has been abetted by an increased and more sophisticated understanding of the composition of the homeless population, the emergence of evidence-based practices to address homelessness, and the passage of the Patient Protection and Affordable Care Act. This article summarizes the evolving understanding of the role that serious mental illness plays in homelessness as well as the interventions that are effective at preventing and ending homelessness among persons with serious mental illness. This summary contextualizes a discussion of the practice and policy agenda to address homelessness among people with serious mental illness using a new prevention framework and considering the opportunities inherent in increased affordable health care coverage for very low-income individuals with serious mental illness.