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Cdk4\/6 inhibition has been shown to induce potent G\n                    <jats:sub>1<\/jats:sub>\n                    arrest in vitro and tumor regression in vivo; cdk2\/1 inhibition has the most potent effects during the S and G\n                    <jats:sub>2<\/jats:sub>\n                    phases and induces E2F transcription factor\u2013dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short half-lives, including those encoding antiapoptosis family members, cell cycle regulators, as well as p53 and nuclear factor-kappa B\u2013responsive gene targets. These effects may account for apoptosis induced by cdk9 inhibitors, especially in malignant hematopoietic cells, and may also potentiate cytotoxicity mediated by disruption of a variety of pathways in many transformed cell types. Current work is focusing on overcoming pharmacokinetic barriers that hindered development of flavopiridol, a pan-cdk inhibitor, as well as assessing novel classes of compounds potently targeting groups of cell cycle cdks (cdk4\/6 or cdk2\/1) with variable effects on the transcriptional cdks 7 and 9. 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