After a decade of exciting promises, the CDK inhibitor flavopiridol has quietly failed in most clinical trials. This review discusses that flavopiridol is a potent inhibitor of global transcription. This explains not only downregulation of numerous proteins, cell cycle arrest and apoptosis but also all pleiotropic and mysterious effects of flavopiridol. Yet, flavopiridol is not just a second actinomycin D. As an inhibitor of transcription with a unique mechanism of action, flavopiridol may have tremendous clinical potentials. This article reviews the molecular and cellular effects of flavopiridol as well as mechanisms of therapeutic and side effects, suggesting its novel clinical applications as a single agent and in drug combinations.