Novel anti-HIV agents that target different stages of the human immunodeficiency virus type 1 (HIV-1) replication cycle are now in clinical trials and have signs of improving our ability to manage HIV-1. This chapter, and the Conference presentation, dealt with the challenges encountered in realizing the optimal benefits of the newer therapeutics to individuals with AIDS and HIV-1 infection receiving highly active antiretroviral therapy (HAART). Emphasis was on the G-protein-coupled seven-transmembrane chemokine receptor, CCR5, as a potentially new therapeutic target and experience with novel CCR5 inhibitors, and the promise from further advancement through structural and molecular analysis of CCR5 inhibitor-CCR5 interactions. The promise in some of the newer protease inhibitors was also discussed.