The notion that homelessness in the United States can be ended, rather than managed, represents a fundamental shift in expectations that has occurred over the past three decades. Many U.S. cities now have plans to end homelessness. Yet homelessness and housing instability are substantial problems that afflict a diverse group of subpopulations such as families, youth, veterans, and chronically homeless single adults. Ending homelessness for each of these populations may require tailored interventions that are responsive to specific individualized needs. These factors make tackling homelessness a difficult task. Although evidencebased solutions exist for some subpopulations, such as housing first for chronically homeless adults, scaling up best practices remains a challenge. For other subpopulations, such as transitional aged youth, evidence-based interventions need to be developed. In this paper we argue that ending homelessness is a Grand Challenge that is big, important, and compelling—one that the profession of social work should be adopt. Meeting this challenge will require a focused, organized response from social work researchers, clinicians, and policymakers. Ending homelessness will require innovation and interdisciplinary or cross-sector collaboration.