The number of drug-drug interactions is remarkably high among hospitalized patients receiving systemic azole antifungal agents. Recent estimates suggest that as many as 95% of hospitalized patients treated with azole antifungals may receive medications capable of producing a major or moderate pharmacokinetic interaction. The antifungal properties of the azoles stem from their propensity to inhibit fungal cytochrome P-450 enzymes. In humans, however, azole antifungals also interfere with several hepatic and intestinal cytochrome P-450 isoenzymes responsible for the metabolism of numerous drugs. As a result, the azole antifungals have drug-drug interactions with a plethora of drug classes, including H(1)-antihistamines, antineoplastics, steroids, antimicrobials, antiretrovirals, opioids, long acting barbiturates, cardiovascular agents, psychotropics and oral contraceptives. These interactions are so numerous that it is extremely difficult to remember them all and would be even harder to prospectively predict their consequences in an individual patient. In fact, any drug that shares the same cytochrome P-450 isoenzymes for metabolism may potentially to give rise to drug-drug interactions in vivo. Patients with specific polymorphisms are probably at especially high risk. Certain drug combinations with azoles should be absolutely avoided, while other combinations may be prescribed provided monitoring of drug levels is undertaken, dosage reduction of one or more of the drugs is made (as appropriate) and/or careful monitoring of clinical parameters is performed.