Syringe exchange programs (SEPs) have been shown to be highly effective in reducing HIV transmission among injection drug users (IDUs). Despite this evidence, SEPs have not been implemented in many communities experiencing HIV epidemics among IDUs. We interviewed 17 key informants in nine U.S. cities to identify factors and conditions that facilitated or deterred the adoption of SEPs. Cities were selected to represent diversity in size, geographic location, AIDS incidence rates, and SEP implementation. Key informants included HIV prevention providers, political leaders, community activists, substance use and AIDS researchers, and health department directors. SEPs were established by one or more of three types of implementation models: (a) broad community coalition support, (b) community activist initiative, and (c) top-down decision making by government authorities. In each model, coalition building and community consultation were critical steps for the acceptance and sustainability of SEPs. When others were not prepared to act, community activists spearheaded SEP development, taking risks in the face of opposition, but often lacked the resources to sustain their efforts. Leadership from politicians and public health officials provided needed authority, clout, and access to resources. Researchers and scientific findings lent force and legitimacy to the effort. Rather than adopting adversarial positions, successful SEP implementers worked with or avoided the opposition. Fear of repercussions and lack of leadership were the greatest barriers to implementing SEPs. Communities that successfully implemented SEPs were those with activists willing to push the agenda, public officials willing to exercise leadership, researchers able to present authoritative findings, and proponents who effectively mobilized resources and worked to build community coalitions, using persistent but nonadversarial advocacy.