IFN regulatory factors (IRFs) are a family of transcription factors that play an essential role in the homeostasis and function of immune systems. Recent studies indicated that IRF-8 is critical for the development of CD11b^lowCD8α⁺ conventional dendritic cells (DCs) and plasmacytoid DCs. Here we show that IRF-4 is important for CD11b^highCD8α^– conventional DCs. The development of CD11b^high DCs from bone marrow of IRF-4^–/– mice was severely impaired in two culture systems supplemented with either GM-CSF or Flt3-ligand. In the IRF-4^–/– spleen, the number of CD4⁺CD8α^– DCs, a major subset of CD11b^high DCs, was severely reduced. IRF-4 and IRF-8 were expressed in the majority of CD11b^highCD4⁺CD8α^– DCs and CD11b^lowCD8α⁺ DCs, respectively, in a mutually exclusive manner. These results imply that IRF-4 and IRF-8 selectively play critical roles in the development of the DC subsets that express them.