Downstream core promoter elements are an expanding class of regulatory sequences that add considerable diversity to the promoter architecture of RNA polymerase II-transcribed genes. We set out to determine the factors necessary for downstream promoter element (DPE)-dependent transcription and find that, against expectations, TFIID and the GTFs are not sufficient. Instead, the protein kinase CK2 and the coactivator PC4 establish DPE-specific transcription in an in vitro transcription system containing TFIID, Mediator, and the GTFs. Chromatin immunoprecipitation analyses using the DPE-dependent IRF-1 and TAF7 promoters demonstrated that CK2, and PC4 are present on these promoters in vivo. In contrast, neither PC4 nor CK2 were detected on the TAF1-dependent cyclin D promoter, which contains a DCE type of downstream element. Our findings also demonstrate that CK2 activity alters TFIID-dependent recognition of DCE sequences. These data establish that CK2 acts as a switch, converting the transcriptional machinery from functioning on one type of downstream element to another.