The Special Populations Networks (SPN) Program was a 5-year, nationwide project funded by the National Cancer Institute to reduce cancer-related health disparities in minority and other underserved communities by building community health infrastructure, improving cancer awareness and use of cancer screening services, and increasing the cadre of minority junior scientists studying disparities issues. Through collaborations with a wide range of community and academic partners, the 18 grantee organizations: 1) developed culturally sensitive cancer communications approaches and materials; 2) conducted outreach and educational activities appropriate to their communities' needs and diverse cultures; and 3) trained and mentored young minority investigators who succeeded in winning support for pilot projects addressing local cancer health disparities issues, trained and deployed lay health workers, and worked with community and health provider organizations to improve understanding of cancer risk in these populations and encourage participation in appropriate clinical trials. SPN activities were grounded in community-based participatory research principles and practice. This overview highlights major project themes, provides examples of differing individual grantee approaches to similar issues, and describes key lessons learned, as reported by the SPN projects, that may guide future programmatic and research efforts to eliminate cancer health disparities in the United States. Cancer 2006. Published 2006 by the American Cancer Society.