This discussion paper outlines the advantages of implementing a combination prevention approach by using the synergies of behavioral, biomedical, and structural interventions. While there have been notable declines in HIV prevalence and incidence linked to behavioral changes in the population, improving these trends will require support for larger and more effective prevention programs. The paper defines combination prevention and outlines necessary steps for planning and implementing a coherent, evidence-informed, and rights-based approach. For planning, the paper highlights using an inclusive, transparent, evidence-informed process; identifying modes of transmission, geographic patterns, and populations; and developing a national plan for combination prevention. Implementation requires understanding and addressing political and capacity barriers and simutaneously working on coordination, quality, and efficiency.Finally, effective implementation requires investments in monitoring and evaluation. Combination prevention is an attempt to address not just the individual causes of vulnerability, but also the underlying social, cultural, legal, and structural causes. This approach requires identification of local solutions and development of coordinated, synergistic, and evidence-based responses; these must be both strategic and sustainable if they are to reach the goal of zero new infections found in many national HIV strategic plans.