Cells of the mononuclear phagocyte lineage include macrophages, microglia, osteoclasts, and myeloid dendritic cells. These cell types are all derived from blood monocytes, which are the product of hematopoietic stem cell differentiation. In this review we use specific examples of macrophage-expressed genes to illustrate potential regulatory strategies for directing macrophage-specific gene expression. The examples we have chosen-the human c-fes gene, the murine spi-1 (PU.1) gene, the human RANTES promoter, and the human CD68 gene-illustrate different aspects of constitutive and inducible gene expression in macrophages. One important challenge for future work in this field will be to identify the molecular events that dictate lineage decisions during the differentiation of mononuclear phagocytes from hematopoietic progenitor cells. Another important goal will be to understand how groups of macrophage genes are coordinately expressed in response to physiological, immunological, and inflammatory stimuli. A better understanding of macrophage gene expression may find application in gene therapy, genetic vaccination, and the development of new antiinflammatory drugs.