Human immunodeficiency virus infection, despite tremendous efforts in research and prevention, is spreading at an increasing speed, especially in developing countries. Currently available therapeutic approaches significantly extend the lifespan of HIV-infected people, but their use is associated with a severe drug regimen, several undesirable side effects, and high cost. Therefore, the scientific community is steadfastly pursuing novel strategies for inhibiting viral replication, promoting a better immune response, and developing an effective vaccine. Recent research on HIV receptors has introduced new concepts in the field, showing that expression of receptors, although necessary for virus entry, is subordinate to quality of expression, so that efficient infection occurs when receptors are properly colocalized. In addition, intracellular signaling triggered by HIV receptors has been shown to play important roles in pathogenesis by inducing apoptosis of bystander cells. Induction of some pathways of intracellular signaling, however, can instead suppress HIV replication, so that modulation of these pathways constitutes an additional target to be exploited for therapy or vaccines. This article reviews the most exciting aspects of these novel findings and discusses their practical application in the fight against HIV infection.