Mature B lymphocytes do not constitute a homogenous pool of cells, and it is now clear that several functionally and developmentally distinct subsets exist. Of these, marginal zone (MZ) B cells are a subset of peripheral B cells that respond vigorously to blood-borne infections, and play a vital role, particularly in host survival of infection by encapsulated bacteria. Their fast activation and differentiation to antibody-secreting plasma cells allows MZ B cells to bridge the gap between innate and adaptive immunity, effected mainly by the more prolific follicular B cells. Like other naturally activated lymphocytes, MZ B cells may also play a role in homeostasis and tolerance, apart from combating infection. Here we will review some of the extracellular signals that affect their development, selection and function. We conclude by examining how their repertoire, location and interactions with other cell types may be important in the induction of autoimmune disease.