T-bet+ B cells have emerged as a key component of the humoral immune response in both infections and autoimmune disorders, with many of their phenotypic and functional attributes conserved between mice and humans. They are protective (infections) and pathogenic (autoimmunity), although the associated commonalities and differences remain unclear. Heterogeneity within this pool, in terms of origin, fate and function may underlie these divergent roles. Their significance is context-dependent-they may constitute a persistent effector memory cell pool, or products of recent primary responses. In both cases however, T-bet+ cells likely represent antigen-experienced progenitors of antibody-secreting cells with multipotent properties. Given their key contributions to both immunity and disease, T-bet+ B cells are an attractive target for vaccination and therapeutic strategies.