Antibodies capable of neutralizing a range of HIV-1 strains appear in some patients several years after initial infection. Klein et al. devise a way to isolate the B cells producing these antiviral antibodies that relies on an epitope displayed on cells. Instead of relying on commonly used HIV-1 envelope soluble-protein baits, the authors use 293T cells displaying a surface HIV-1 protein spike to screen peripheral blood B cells from volunteers infected with HIV-1. Most antibodies isolated by this new method bind to surface-bound but not soluble HIV-1 envelope proteins, suggesting that they would have been missed in screens using soluble baits. Moreover, the newly identified antibodies neutralize HIV-1 strains that are resistant to antibodies isolated some time before from the same volunteers, and seem to bind to a previously unrecognized site on the HIV-1 spike. By revealing the full spectrum of naturally arising HIV-1–neutralizing serologic activity, this strategy may aid the design of vaccine immunogens for HIV-1 and potentially other pathogens. (J. Exp. Med. 209, 1469–1479, 2012)