The disproportionate burden of cancer among U.S. Hispanics is well documented. Historically, epidemiologic data on U.S. Hispanics and cancer have aggregated all Hispanics as one homogeneous group without appreciating the diversity of this population with regard to nativity (nationality/geographic origin). The authors report on the initial efforts of a collaborative academic institutional partnership between a minority-serving institution and a National Cancer Institute-designated cancer center to address cancer health disparities in two Hispanic communities in Puerto Rico and Florida. This article outlines the joint Outreach Program's initial collaborative strategies and activities in community outreach, cancer education, and research that mutually benefit both the Ponce (Puerto Rico) and Tampa (Florida) Hispanic communities. This partnership program used innovative multipronged community-engagement strategies in the two communities to reduce cancer health disparities. Specific projects and lessons learned from three outreach/cancer education projects and two pilot research projects are discussed. The challenges of balancing service and research agendas in communities with disparate levels of resources and infrastructure are summarized to inform future initiatives in this partnership, as well as serve as an example for similar minority-serving institution/cancer center partnerships to reduce cancer health disparities.