Studying the structures of antibodies bound to viral proteins provides clues that can direct vaccine design. Now for the first time, Corti et al. report the discovery of a monoclonal antibody (mAb) that neutralizes the two known groups of influenza A viruses and structural features of the mAb's pan-influenza cross-reactivity. To discover the rare cells that produced such a mAb, the authors individually screened 104,000 human plasma cells from eight donors previously found to produce strong antibody responses against a broad range of virus subtypes. This effort yielded a single mAb FI6 that bound all tested recombinant or purified influenza hemagglutinin (HA) proteins. The authors then stained cells that were transfected with recombinant HA genes and neutralized viruses from both influenza groups. FI6 was shown to be effective prophylactically and therapeutically in mice against H1N1 and H3N2 strains of influenza, and in ferrets as a prophylactic against a highly pathogenic H5N1 strain. Mutagenesis and structural studies, including co-crystallization of HA proteins from both influenza groups with fragments of an optimized FI6, revealed that the broadly neutralizing activity of the mAb is related to its ability to bind a particular conserved region. (Science 333, 850–856, 2011)