While a successful HIV vaccine will likely take several more years to become a reality, many anti-retroviral (ARV) drugs are currently available to treat HIV infection, and their efficacious use has improved the quality of life and life expectancy of millions of HIV-infected individuals. A recent addition to these ARVs is a new class of drug that targets the HIV entry process by interfering with the action of the CCR5 coreceptor. The first licensed member of this class is a drug called maraviroc, which is also the first ARV that targets a cellular rather than a viral protein. Several other CCR5 antagonists with varied mechanisms of action are being developed. Key issues with the use of these drugs include determining their potential for use in treatment-naïve versus treatment-experienced patients, the development of sensitive coreceptor phenotyping assays to determine patient eligibility, and finally monitoring the emergence of resistant viruses and their mechanisms of resistance. This review summarizes the preclinical and clinical development of maraviroc as well as studies of HIV resistance to this drug both in vitro and in patients. In addition, a range of diverse CCR5 antagonists currently under development, are also discussed.