During myeloid differentiation, the pluripotent hematopoietic stem cell passes through several well-defined morphologic stages within the bone marrow. These changes include progressive nuclear segmentation and the acquisition of stage-specific granules. Primary granules appear at the myeloblast stage, and are found in both neutrophils and monocytes. At the myelocyte stage, neutrophil precursors acquire specific granules, a marker of commitment to terminal neutrophil differentiation. This complex developmental pathway is just beginning to be elucidated. Current evidence suggests that myeloid differentiation is regulated primarily by transcriptional regulatory proteins, and that dysfunction of those regulators is involved in most disorders of neutrophil maturation. Furthermore, there is evidence that study of late gene expression may provide insights into more proximal events in granulocytic maturation. In this review, we provide a brief overview of myeloid differentiation with emphasis on the culture systems available for the study of granulopoiesis and the insights they provide into the regulation of late neutrophil-specific gene expression. We discuss the relevance of these observations to our understanding of the pathogenesis of defects in neutrophil differentiation.