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. 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 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.