People experiencing homelessness are disproportionately affected by infectious diseases and often face barriers to receiving appropriate medical treatment. Responding to the needs of people experiencing homelessness requires state and local health departments to integrate information sources and coordinate multisector efforts. From 2021 to 2023, the CDC Foundation, in cooperation with the Centers for Disease Control and Prevention, established pilot Centers of Excellence in Public Health and Homelessness in Seattle, Washington; San Francisco, California; and the state of Minnesota. These centers strengthened their capacity to address the needs of people experiencing homelessness by supporting cross-sector partnerships, assessing the interoperability of data systems, prioritizing infectious disease needs, and identifying health disparities. These programs demonstrated that health departments are heterogeneous entities with differing resources and priorities. They also showed the importance of employing dedicated public health staff focused on homelessness, establishing diverse partnerships and the need for support from local leaders to address homelessness.