Patients with acid-related diseases often need to take multiple medications. Treatment of Helicobacter pylori infection often includes either a histamine type 2 (H2)-receptor antagonist or a proton pump (H+,K+-ATPase) inhibitor (proton pump inhibitor), administered in conjunction with one or more antimicrobials. Also, treatment for acid-related diseases often requires extended therapy during which many concomitant medications may be administered for concurrent disease states. Polypharmacy may be the result, particularly in elderly patients, who are at increased risk for both acid-related and many other diseases. Thus, it is important to understand the potential for clinically significant drug–drug interactions in this setting. H2-receptor antagonists and proton pump inhibitors can influence the pharmacokinetic profiles of other commonly administered medications by elevating intragastric pH, which can alter drug absorption, and by interacting with the cytochrome P (CYP) 450 enzyme system, which can affect drug metabolism and clearance. Such interactions are particularly important when they affect the pharmacokinetics of drugs with narrow therapeutic ranges (e.g. warfarin, digoxin). In these cases, drug–drug interactions can result in significant toxicity and even death. There are marked differences among H2-receptor antagonists and proton pump inhibitors in their potential for such interactions. The oldest drugs in each class, cimetidine and omeprazole, respectively, have the greatest potential to alter CYP activity and change the pharmacokinetics of other drugs. The most recently developed H2-receptor antagonist, famotidine, and the newer proton pump inhibitors, rabeprazole and pantoprazole, are much less likely to induce or inhibit CYP and thereby change the metabolism of other medications. These differences are important when choosing medications for the safe treatment of patients with acid-related diseases.