AIDS has claimed the lives of over 25 million people, driving the continuing desire to identify new treatments for this devastating disease. Maraviroc, the first CC Chemokine Receptor 5 (CCR5) antagonist to be licensed as a treatment for HIV, works by blocking cellular entry by the virus through CCR5. This chapter describes the rationale for the approach and the medicinal chemistry that eventually led to the discovery of maraviroc, including the removal by design of unwanted CYP2D6 and hERG activity. The use of structure-based drug design to develop follow-on agents and series is also described. Clinical data for maraviroc are provided, and the development of other CCR5 antagonists discovered across the pharmaceutical industry is summarized.