Cyclin-dependent kinases (CDKs) are required for replication of adeno-, papilloma-and other viruses that replicate only in dividing cells. Surprisingly, CDKs are also required for replication of HIV-1, HSV-1, and other viruses that can replicate in non-dividing cells. Since two low-molecular weight pharmacological CDK inhibitors (PCIs), flavopiridol (Flavo) and roscovitine (Rosco), appear to be non-toxic in human clinical trials against cancer, these drugs have been proposed as potential antiviral drugs. Rosco preferentially inhibits CDKs involved in cell cycle regulation (CDK1, 2, and 7) or neuronal functions (CDK5), whereas Flavo preferentially inhibits CDKs involved in cell cycle (CDK1, 2, 4, 7) or transcription (CDK7, and 9). As potential antivirals, PCIs display several advantages: (i) they are active against many different viruses, including drug-resistant strains of HIV-1 and HSV-1; (ii) PCI-resistant mutants of HIV-1 or HSV-1 have not been identified; and (iii) the antiviral effects of PCIs and conventional antivirals appear to be additive (as expected from drugs that target independent pathways). Moreover, PCIs target both the etiological agents (i.e., the virus) and the pathogenic mechanisms (i.e., unrestricted cell division) of the many diseases that include both a CDK-requiring virus and unrestricted cell division (e.g., Kaposi's sarcoma, cervical carcinoma, HIV-associated nephropathy-HIVAN). This is nicely illustrated in a recent study which demonstrated the efficacy of Flavo in a mouse model of HIVAN. Herein, we will review the involvement of CDKs in viral replication and the antiviral properties of the most extensively characterized PCIs, with special emphasis on the mechanisms of inhibition of viral transcription.