Perturbations in myelopoiesis are a common feature in solid tumor biology, reflecting the central premise that cancer is not only a localized affliction but also a systemic disease. Because the myeloid compartment is essential for the induction of adaptive immunity, these alterations in myeloid development contribute to the failure of the host to effectively manage tumor progression. These "dysfunctional" myeloid cells have been coined myeloid-derived suppressor cells (MDSCs). Interestingly, such cells not only arise in neoplasia but also are associated with many other inflammatory or pathologic conditions. MDSCs affect disease outcome through multiple mechanisms, including their ability to mediate generalized or antigen-specific immune suppression. Consequently, MDSCs pose a significant barrier to effective immunotherapy in multiple disease settings. Although much interest has been devoted to unraveling mechanisms by which MDSCs mediate immune suppression, a large gap has remained in our understanding of the mechanisms that drive their development in the first place. Investigations into this question have identified an unrecognized role of interferon regulatory factor-8 (IRF-8), a member of the IRF family of transcription factors, in tumor-induced myeloid dysfunction. Ordinarily, IRF-8 is involved in diverse stages of myelopoiesis, namely differentiation and lineage commitment toward monocytes, dendritic cells, and granulocytes. Several recent studies now support the hypothesis that IRF-8 functions as a "master" negative regulator of MDSC formation in vivo. This review focuses on IRF-8 as a potential target suppressed by tumors to cripple normal myelopoiesis, redirecting myeloid differentiation toward the emergence of MDSCs. Understanding the bases by which neoplasia drives MDSC accumulation has the potential to improve the efficacy of therapies that require a competent myeloid compartment.