Abstract: HIV infection, viral hepatitis, sexually transmitted diseases, and tuberculosis in the United States remain major public health concerns. The current disease-specific prevention approach oftentimes has led to narrow success and missed opportunities for increasing program capacity, leveraging resources, addressing social and structural determinants, and accelerating health impact—suggesting a need for greater innovation to prevent related diseases. The National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention’s Program Collaboration and Service Integration (PCSI) strategic priority aims to strengthen collaborative engagement across these disease areas and to integrate services at the client level. In this review, we articulate the 5 principles of PCSI—appropriateness, effectiveness, flexibility, accountability, and acceptability. Drawing upon these principles and published literature, we discuss the case for change that underlies PCSI, summarize advances in the field since 2007, and articulate key next steps. Although formal evaluation is needed to fully assess the health impact of PCSI, available evidence suggests that this approach is a promising tool to advance prevention goals.