CDK8 belongs to a group of cyclin-dependent kinases involved in transcriptional regulation from yeast to mammals. CDK8 associates with the Mediator complex, but functions outside of Mediator are also likely. Historically, CDK8 has been described mostly as a transcriptional repressor, but a growing body of research provides unequivocal evidence for various roles of CDK8 in gene activation. Several transcriptional programs of biomedical importance employ CDK8 as a co-activator, including the p53 network, the Wnt/β-catenin pathway, the serum response network, and those governed by SMADs and the thyroid hormone receptor, thus highlighting the importance of further investigation into this enigmatic transcriptional regulator.