Although extraordinary progress has been made in the treatment and prevention of HIV infection, the AIDS pandemic continues to rage globally with 2.1 million infections and 1.6 million AIDS-related deaths reported in 2013. Until an effective vaccine is developed, new strategies for treatment and prevention are needed. Regarding the prevention of HIV infection, a major focus of prevention research in general and vaccine research in particular involves the interaction of the HIV-1 envelope protein gp120 with cell-surface receptors, with the hope that a greater understanding of these interactions will lead to the development of novel strategies aimed at preventing and even treating HIV-1 infection. Particular attention has been directed toward gaining a more precise understanding of the early events in transmission focusing on that critical window of time when HIV first establishes infection in the host. Here we describe some of the recent findings involving HIV-1 envelope interactions with cell surface receptors that are relevant to transmission and which may represent new opportunities to develop strategies to prevent HIV infection.