In spite of the unquestionable positive impact of HAART in the treatment of HIV infection, the discovery and development of novel agents directed towards other targets of the replicative cycle of the virus that differ from those targeted by the clinically approved drugs, emerges nowadays as an imperative need. The blockade of HIV entry is a highly promising strategy against the pathogen and glycoprotein gp120 is a central actor in this process. This review discusses the current status in the research of anti-HIV agents targeting specifically the envelope protein gp120. The diverse approaches devoted to the achievement of therapeutic agents against gp120 currently under study are organized and analyzed critically according to their specific mechanism of inhibition and structural features.