Haynes et al. discuss recent findings in Science and Nature Medicine about antibodies directed to the membrane-proximal region (MPR) of the HIV-1 envelope (ENV) glycoprotein and their possible therapeutic utility. Although these antibodies have the desirable trait of neutralizing the virus in vitro, they occur only rarely in patients, possibly because they also react with self-antigens such as the lipid cardiolipin, and so are eliminated. In addition, the MPR region of HIV-1 may not be accessible to this antibody in patients, limiting its usefulness. Nevertheless, Haynes et al. indicate that further work on neutralizing antibodies that target the conserved Env protein of HIV-1 is warranted.