In the marginal zone of the spleen the bloodstream passes through an open system of reticular cells and fibers in which various myeloid and lymphoid cells are located. Macrophages in this region are well equipped to recognize pathogens and filter the blood by virtue of unique combinations of pattern recognition receptors. They interact with a specific set of B cells that can be found only in the marginal zone and that are able to react rapidly to bacterial antigens in particular. This combination of strategically located cells is an important factor in our defense against blood-borne pathogens. New data on the development of the marginal zone itself and the marginal zone B cells are reviewed and discussed in light of the function of the spleen in host defense.