Current therapeutic intervention in HIV infection relies upon over 30 different therapeutic options. Despite the efficacy shown by these drugs, clinicians are confronted with an unexpected frequency of adverse effects and resistance, including transmitted resistance. There is now a great need for new drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus. Drugs that target the interactions between the HIV envelope and the cellular receptor complex are a ‘new entry’ into the scenario of HIV therapy and have recently raised great interest because of their activity against multidrug-resistant viruses. Two such drugs include maraviroc, a CCR5 antagonist, and enfuvirtide, a fusion inhibitor, both of which work via separate mechanisms to block the entry of HIV into the cell. The clinical pharmacology, and studies of efficacy and safety of these two agents, and investigational drugs within this class, are described in this current chapter.