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.