Here, Bruzzone et al. explore the relative contributions of the transcriptional coactivators Mediator and two histone acetyltransferase (HAT) complexes, NuA4 and SAGA, to RNA polymerase II association at specific genes and gene classes by rapid nuclear depletion of key complex subunits. They show that the NuA4 HAT Esa1 differentially affects certain groups of genes, whereas the SAGA HAT Gcn5 has a weaker but more uniform effect, and their findings suggest that at least three distinct combinations of coactivator deployment are used to generate moderate or high transcription levels.