Decades ago, medical researchers noted that non‐steroidal anti‐inflammatory drugs (NSAIDs), for example aspirin and indomethacin, modulate primary herpesvirus infections and diminish reactivation of latent herpesvirus infections. NSAIDs inhibit cyclooxygenase (COX) enzymes, molecules necessary for generation of prostaglandins. Numerous studies indicate that herpesvirus infections elicit elevated levels of cyclooxygenase 2 (COX‐2) with a resultant increase in prostaglandin E₂ levels (PGE₂). Thus, the biochemical pathway underlying the anti‐herpetic mechanism of NSAIDs is linked to the inhibition of COX. The precise roles of COX‐2 and PGE₂ in the viral life cycle are unknown. However, among the alphaherpesvirus, betaherpesvirus and gammaherpesvirus subfamilies, evolutionarily conserved mechanisms ensure modulated expression of COX molecules, underscoring their importance in viral replication and virus–host interactions. Copyright © 2006 John Wiley & Sons, Ltd.