Macrophage populations exhibit a wide range of antigenic and functional phenotypes, including cytokine production, response to immunomodulatory stimuli, and clearance of pathogens. The expanding clinical exploitation of recombinant growth factors and cytokines with the potential to regulate the production and function of peripheral macrophage populations necessitates an increased understanding of the mechanisms by which functionally distinct macrophage populations arise as well as the ramifications of macrophage heterogeneity. The present review summarizes recent data which supports multiple mechanisms by which heterogeneous macrophage populations arise: 1) differential signals experienced within diverse tissue microenvironments; 2) developmentally-staged expression of specific functions; 3) clonal variation of myeloid progenitor cells; and 4) alternate hematopoietic stimulation. These data show that the above processes are not mutually exclusive and that each likely contributes to the observed heterogeneity of peripheral macrophage populations.