The transcription factor, interferon regulatory factor-8 (IRF8), is required for the development of monocytes, macrophages, dendritic cells (DCs), basophils, and eosinophils, while it inhibits the generation of neutrophils. Recently, the molecular mechanisms by which IRF8 regulates their development have been increasingly clarified by genome-wide analyses, including chromatin immunoprecipitation-sequencing and transcriptome profiling. IRF8 associates with the myeloid master transcription factor, PU.1, to promote the establishment of cell-type-specific enhancers and gene expression, thereby driving monocyte development or maintaining the plasmacytoid DC-specific gene expression profiles. Furthermore, microbial stimulation enables IRF8 to associate with other transcription factors, including IRF1, to induce immune response genes. Knowledge about the regulation of Irf8 expression in myeloid development has also increased. In this review, we discuss recent advances in our understanding of transcriptional and epigenetic regulation involving IRF8 in the development of myeloid cells.