Since the identification of CCR5 and CXCR4 as HIV coreceptors a little over a decade ago, there has been hope that coreceptor inhibitors will be able to make an impact on the HIV epidemic, both as novel therapeutic drugs and as agents used in prevention. Significant progress has been made in the understanding of how coreceptor choice might impact HIV pathology and how coreceptor blockade may affect health. In this review, we focus on some of the key issues that are emerging now that CCR5 has been validated as a promising target for HIV prevention strategies and at a time when a CCR5 inhibitor has been approved in the United States as the first in a new class of anti-HIV therapeutic drugs.