The newer oral antifungal agents, such as fluconazole, itraconazole and terbinafine, are generally both effective and well tolerated in the management of widespread or resistant dermatomycoses such as onychomycosis. However, these agents differ markedly in their potential to cause clinically significant drug interactions. Triazoles such as fluconazole and itraconazole have been responsible for a greater number of clinically significant drug interactions than terbinafine. For example, itraconazole, and to a lesser extent fluconazole (in high doses) are inhibitors of CYP3A4. Therefore certain agents that are substrates of this enzyme, such as some of the new generation of H1-antihistamines, several HMG-CoA reductase inhibitors and certain benzodiazepines, are contraindicated. Other drugs like cyclosporine and quinidine need careful monitoring if administered concurrently with these triazoles. In contrast, there are no drug-drug contraindications with terbinafine. Indeed, in a postmarketing surveillance study, in which 42.8% of the 25,884 participating patients were taking a variety of concomitant therapies, no new drug-drug interactions were revealed. Physicians should be aware of the potential for interaction of the medications that they prescribe, in order to prevent or reduce the burden of adverse events. Terbinafine may be the most rational choice of oral antifungal agent in patients receiving concomitant medications that may adversely affect or be affected by either fluconazole or itraconazole.