Combination HIV prevention is of high priority for increasing the impact of partially efficacious HIV prevention interventions for specific populations and settings. Developing the package requires critical review of local epidemiology of HIV infection regarding most-impacted populations and those at high risk of HIV transmission and acquisition, drivers of HIV infection, and available interventions to address these risk factors. Interventions should be considered in terms of the evidence basis for efficacy, potential synergies, and feasibility of delivery at scale, which is important to achieve high coverage and impact, coupled with high acceptability to populations, which will impact uptake, adherence, and retention. Evaluation requires process measures of uptake, adherence, retention, and outcome measures of reduction in HIV infectiousness and acquisition. Three examples of combination prevention concepts are summarized for men who have sex with men in the Americas, young women in sub-Saharan Africa, and HIV serodiscordant couples.