Differential gene expression gives rise to the many cell types of complex organisms. Enhancers regulate transcription by binding transcription factors (TFs), which in turn recruit cofactors to activate RNA Polymerase II at core promoters. Transcriptional regulation is typically mediated by distinct combinations of TFs, enabling a relatively small number of TFs to generate a large diversity of cell types. However, how TFs achieve combinatorial enhancer control and how enhancers, enhancer-bound TFs, and the cofactors they recruit regulate RNA Polymerase II activity is not entirely clear. Here, we review how TF synergy is mediated at the level of DNA binding and after binding, the role of cofactors and the post-translational modifications they catalyze, and discuss different models of enhancer—core-promoter communication.