Patients with complex medical and drug histories are becoming more commonplace in dental practice. This article reviews three serious adverse drug interactions that are well supported by the literature and can impact dental practice. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the renal excretion of lithium and lead to lithium toxicity. Metronidazole and fluconazole inhibit the metabolism of warfarin by blocking cytochrome P-450 2C9 (CYP-2C9), the major metabolic pathway of warfarin, with the end result being dramatic increases in patients' international normalized ratios (INRs) and potentially fatal bleeding. Propranolol and other nonselective beta-adrenergic blocking agents can inhibit the vasodilatory effect of epinephrine in dental local anesthetic solutions, leading to hypertensive reactions and a concomitant reflex bradycardia. It is important for clinicians to recognize and avoid these serious drug interactions. By doing so, they will provide the safest and best treatment for their patients.