It is now clear that functionally distinct subsets of mature peripheral B cells exist. Of these subsets, marginal zone (MZ) B cells in the spleen are strategically positioned at the blood–lymphoid interface and are programmed to initiate a fast and intense antibody response to blood‐borne viral and bacterial agents. Their ability to respond vigorously to antigen and polyclonal activators make MZ B cells key players in the early response to pathogens in the bloodstream. The specialized functions of these innate‐like lymphocytes bridge the gap between the early innate immune response and the slower adaptive antibody response, affected mainly by the more prolific follicular B cells. MZ B cells, like B1 cells, are important not only to combat infections but also in the maintenance of host homeostasis. Here we discuss some aspects of MZ B‐cell selection and function in health and disease.