Ten cyclin-dependent kinases (CDK1–CDK10) are currently known, of which only CDKs 1, 2, 3, 4, and 6 intervene directly in the cell cycle, while CDK7 plays an indirect role as an activator of these CDKs. CDK1 controls G2/M transition and CDK2, CDK3, CDK4, and CDK6 are implicated at G1/S. Furthermore, CDK7, CDK8, CDK9 act as regulators of transcription. Both CDK7 and CDK8 phosphorylate the large subunit of RNA polymerase II, required for elongation. CDK9 is a component of the transcription factor P-TEFb. Moreover, CDK8/cyclin C also represses transcription by phosphorylating cyclin H and negatively regulating TFIIH kinase activity, and it has been reported that the inhibitor flavopiridol potently inhibits transcription (IC50 < 10 nM) in vitro. Since that the function of protein is determined essentially by its corresponding three-dimensional (3D) structure, the human cyclin-dependent kinase 8 (CDK8) structures complexed with ATP and flavopiridol have been modelled using human CDK2 as template. The three-dimensional structure of CDK2 provides a structural foundation for understanding the mechanisms of activation and inhibition of CDK2 and for the discovery of inhibitions. Model building of the complexes were carried out using the program Parmodel, which is a web server for automated modeling and protein structural assessment. Parmodel runs a parallelized version of MODELLER. We have constructed three-dimensional models of the CDK8 by comparative molecular modeling, and these models are further assessed by Verify-3D and Procheck. The structures have been compared with other CDK structure, and the results show that these models are reliable. The CDK8 models are folded into the typical bilobal structure, with the smaller N-terminal lobe consisting predominantly of b-sheet structure and the larger C-terminal lobe consisting primarily of a-helices. The central role of CDKs as regulators of transcription makes them a promissing target for discovering small inhibiting molecules that can modify the degree of RNA transcription.