Mammalian GCN5 and PCAF are paralogous histone acetyltransferases important for normal development, cell proliferation, and differentiation. GCN5/PCAF function as part of STAGA-type complexes that regulate chromatin structure and transcription. Here we identify and characterize novel GCN5/PCAF-associated cofactors in human cells and show that GCN5 and PCAF incorporate similarly into two distinct types of complexes: the prototypical STAGA (SPT3-TAF9-GCN5/PCAF Acetylase) coactivator complex and the novel ATAC (ADA Two A Containing) complex. We demonstrate the importance of STAGA's core component, STAF65γ, in maintaining the structural integrity of the STAGA complex and activating MYC-dependent transcription. Furthermore, we show that human ATAC carries both acetyltransferase and kinase activities and integrates components of several different types of proteins including chromatin/transcription coregulators and mitogen-activated protein kinase signaling. In addition, human ATAC contains a novel YEATS2/NC2β histone fold module that interacts with the TATA-binding protein (TBP) and negatively regulates transcription when recruited to a promoter. Our results suggest that vertebrate STAGA-type and ATAC-type complexes link specific extracellular signals to modification of chromatin structure and regulation of the basal transcription machinery.