The mechanisms regulating the induction and maintenance of B lymphocytes have been delineated extensively in immunization studies using proteins and hapten-carrier systems. Increasing evidence suggests, however, that the regulation of B cell responses induced by infections is far more complex. In this study, we review the current understanding of B cell responses induced following infection with influenza virus, a small RNA virus that causes the flu. Notably, the rapidly induced, highly protective, and long-lived humoral response to this virus is contributed by multiple B cell subsets, each generating qualitatively distinct respiratory tract and systemic responses. Some B cell subsets provide extensive cross-protection against variants of the ever-mutating virus, and each is regulated by the quality and magnitude of infection-induced innate immune signals. Knowledge gained from the analysis of such highly protective humoral response might provide a blueprint for successful vaccines and vaccination approaches.