The demand for new treatment options against HIV is becoming increasingly desperate as the side effects and the expansion and spread of drug-resistant virus within the infected population limit the clinical benefits provided by available anti-HIV drugs. Preparations of polyclonal antibodies have a long history of proven clinical utility against some viruses; however, they have enjoyed very limited success against HIV. Recent clinical trials and in vitro experiments suggest that monoclonal antibodies against HIV may have promise clinically. These antibodies and antibody-based reagents target either the viral envelope glycoprotein, the receptor (CD4) or coreceptor (CCR5) molecules, or transition-state structures that appear during viral entry. The challenge is whether an antibody-based therapy can be identified (with or without their small molecule brethren) that presents long-term clinical efficacy, low toxicity and minimal risk of clinical failure from viral resistance.