By regulating protein degradation, constitutive proteasomes (CPs) control practically all cellular functions. In addition to CPs, vertebrates express immunoproteasomes (IPs). The major nonredundant role ascribed to IPs is their enhanced ability to generate antigenic peptides. We report that CPs and IPs differentially regulate the expression of >8000 transcripts in maturing mouse dendritic cells (DCs) via regulation of signaling pathways such as IFN regulatory factors, STATs, and NF-κB. IPs regulate the transcription of many mRNAs and maturation of a few of them. Moreover, even when engineered to present optimal amounts of antigenic peptide, IP-deficient DCs are inefficient for in vivo T cell priming. Our study shows that the role of IPs in DCs is not limited to Ag processing and reveals a major nonredundant role for IPs in transcription regulation. The dramatic effect of IPs on the transcriptional landscape could explain the various immune and nonimmune phenotypes observed in vertebrates with IP deficiency or mutations.