© Copyright 2015, Mary Ann Liebert, Inc. 2015. Efforts to decrease the spread of HIV worldwide continue at a rapid pace. With the development of new biomedical interventions and findings from pivotal clinical trials, a new framework for short-term and long-term prevention strategies is emerging. It is clear that biomedical-based approaches targeted at the highest risk populations have the greatest potential to have a short-term impact. Unfortunately, challenges with adherence in healthy populations at risk are now well-recognized, and competing health care priorities in the context of fragile delivery infrastructures pose formidable obstacles to implementation. We need better ways to identify high-risk populations, sophisticated understanding of the behavioral parameters that can ensure adherence, and the development of better strategies to provide sustained delivery of preexposure prophylaxis (PrEP). In the long term, we need an effective vaccine - a path that has proven to be rocky. Research facilitating an increased understanding of immune responses and what represents effective responses to prevent HIV acquisition should facilitate progress. While we wait for that time, PrEP offers the best strategy for short-term impact.