All physicians, including dermatologists, are at risk for prescribing drugs that interact in a harmful way. Although prescribing a harmful drug combination may have serious consequences, no review has examined the drug-drug combinations that are of greatest concern for dermatologists. Our goal is to review the pharmacologic mechanisms of adverse drug interactions, the risky drugs, and the patients who are most vulnerable. In so doing, we hope to provide guidance through a potential minefield of adverse interactions. Although there are only sparse epidemiologic data regarding the prevalence or cost of adverse drug interactions in dermatology, the consequences may range from a minor loss of therapeutic effect of an administered agent to a life-threatening toxic reaction. We will review methotrexate, cyclosporin A, antifungal agents, antibiotics, retinoids, and antihistamine interactions with each other and with other systemic medications. An organized reporting system needs to be developed so that statistically meaningful epidemiologic data can be obtained for adverse drug interactions, such as the Medwatch program recently proposed by the Food and Drug Administration. Such a system will provide valuable data regarding drug combinations that may be dangerous and determine the scope of the problem as a public health issue.