Antihistamines and their drug-drug interactions are reviewed in depth. The metabolism of "classic" or sedating antihistamines is coming to light through in vivo and in vitro studies. The polymorphic CYP 2D6 metabolic enzyme appears to be potently inhibited by many of these over-the-counter medications. The history of the discontinued "second-generation" antihistamines terfenadine and astemizole is reviewed to remind the reader why the understanding of the cytochrome P450 system became increasingly important when the cardiotoxicity of these drugs became apparent. The "third-generation" nonsedating antihistamines are also listed and compared. They have been exhaustively scrutinized for drug-drug interactions and cardiotoxicity, and they appear to have no serious drug-drug interactions at recommended doses.