Memory B cells are more heterogeneous than previously thought. Given that B cells play powerful antibody-independent effector functions, it seems reasonable to assume division of labor between distinct memory B cells subpopulations in both protective and pathogenic immune responses. Here we review the information emerging regarding the heterogeneity of human memory B cells. A better understanding of this topic should greatly improve our ability to target specific B cell subsets either in vaccine responses or in autoimmune diseases and organ rejection among other pathological conditions where B cells play central pathogenic roles.