The discoveries that synthetic peptides corresponding to the N- and C-terminal heptad repeat (HR) regions of gp41 have potent anti-HIV activity opened a new avenue to identification of small molecule HIV entry inhibitors targeted to the HIV gp41 coiled-coil regions. Based on the structural information of the HIV gp41 core, three distinct approaches to develop small molecule anti-HIV agents have been reported. Each of these approaches has specific advantages, which will have complementary effects on the design of new strategies for identification of more potent HIV entry inhibitors. It is expected that novel antiviral drugs targeted to the HIV gp41 coiled-coil regions will be developed in the near future for the chemotherapy and/or prophylaxis of HIV infection and AIDS.