Although most studies on murine dendritic cell (DC) differentiation concentrate on the nature of the DC precursor population and the lineage relationship between DC and other hematopoietic cell types, very little research addresses the nature of the microenvironments necessary for DC hematopoiesis. Evidence supporting a major contribution of niches in DC differentiation within hematopoietic tissues is reviewed. A model is presented that identifies a potential role for multiple hematopoietic niches in DC differentiation. It is proposed that multiple DC subsets develop from one or a small number of DC progenitor types that lodge in various niches within different tissue sites. Implications of a niche-mediated model for differentiation of DC precursors are discussed in the context of both physiological and pathological situations. (C) 2004 International Society for Experimental Hematology. Published by Elsevier Inc.