Although all the cells in an organism contain the same genetic information, differences in the cell phenotype arise from the expression of lineage‐specific genes. During myelopoiesis, external differentiating signals regulate the expression of a set of transcription factors. The combined action of these transcription factors subsequently determines the expression of myeloid‐specific genes and the generation of monocytes and macrophages. In particular, the transcription factor PU.1 has a critical role in this process. We review the contribution of several transcription factors to the control of macrophage development. J. Leukoc. Biol. 63: 405–417; 1998.