Activation of transcription requires an interplay between enhancer-binding factors and components of the general transcription machinery, New developments within the past few years suggest that novel cofactors are required for relaying specific activation signals to the RNA polymerase II transcription complex in order to achieve enhanced levels of mRNA synthesis. The role of these different cofactors in mediating activation and potential differences in their utilization by divergent organisms, however, raise new questions about the mechanisms of transcriptional regulation.