In 2003 the first virus entry inhibitor, the anti-HIV peptide T20 (Fuzeon®, enfuvirtide®), was approved for treatment of advanced Human Immunodeficiency Virus Type 1 infection. T20 is an unconventional antiviral drug, as it does not target a viral replicase or protease but a conformational transition within the HIV1 fusion protein gp41 required for virus-cell membrane fusion. Beyond membrane fusion, numerous early drug targets have been identified that will allow for large scale screening or structure-based drug design. The first encounter of the virus with the host might be through binding to attachment receptors, such as the C-type lectins DC- and L-SIGN, which might play an important role of infection for a large number of enveloped viruses by capturing, concentrating and transmitting infectious virions. Once a virus reaches its target cell, a cascade of events generally starting with the interaction of viral envelope glycoproteins with specific entry receptors and co-receptors is necessary in order to trigger the virus-cell membrane fusion. The present review will highlight recent advances in the identification of new drugs and targets at the level of virus entry for three major human pathogens accounting for several hundred million infections worldwide: HIV, Dengue Virus and Hepatitis C virus.