One million Americans are living with HIV/AIDS and 50,000 Americans per year are newly infected with the disease.  The evolution of multi-drug resistant HIV makes the virus difficult to target without combination therapy, and there is a need for new inhibitors of HIV-1 replication.  Moreover, the toxicities associated with available HAART regimens remains a considerable problem.  Current targets for most standard HIV therapies include the viral enzymes reverse transcriptase and protease.  Recently, a new class of viral integrase inhibitors has become available for use in the clinic.  Emerging drug targets for HIV therapies include inhibitors that directly or indirectly block the function of the HIV-1 Env complex, responsible for entry of the virion into the host cell (so-called entry inhibitors).  Using a combination of computer-aided drug discovery protocols and in vitro testing, the Cocklin lab has identified new small molecules that inhibit HIV entry into cells with low nanomolar potency.