MicroRNA (miRNA) play important roles in the development and physiological function of hematopoietic stem/progenitor and mature cell lineages. In addition, deregulated miRNA expression and subsequent gene expression changes are associated with hematologic diseases including myelodysplastic syndromes and acute myeloid leukemia. This review focuses on myelopoiesis as a model to highlight the involvement of miRNA in the regulation of normal and malignant cellular signaling pathways. By incorporating miRNA regulation into well-established myeloid signal transduction pathways, we hope to shed light on targetable factors both upstream and downstream of miRNA signaling. These pathway-specific miRNA functions suggest scenarios wherein miRNA-based therapeutics may be beneficial either alone or in combination with current therapies. J. Cell. Physiol. 227: 525–533, 2012. © 2011 Wiley Periodicals, Inc.