The fundamental concepts surrounding B cells with inhibitory function (regulatory B cells) are now being established. In the context of autoimmune and inflammatory animal models, B cells play an immunomodulatory role via IL-10 production and contribute to limitation of the pathogenesis. Recent studies have notably identified the human counterparts of these cells, which have been suggested to be relevant to the pathophysiology of disease. Clear criteria to identify these cell subsets and the key molecular mechanisms underlying their physiological features are required for understanding the big picture of regulatory B cells. Plasmablasts have recently been identified as a major IL-10-producing regulatory B-cell subset and Ca²⁺ signaling has furthermore been found to contribute to B-cell IL-10 expression. In this review, the signaling components controlling IL-10-dependent B-cell regulatory function and the development of IL-10-competent/-producing B cells and plasmablasts are discussed.