A dentist is often faced with the decision whether to use antibiotics prior to dental procedures to prevent an infection in the patient at a distant site. The rationale for prophylactic antibiotic use is based in biologic plausibility as bacteria from the mouth have been implicated in severe infections in other parts of the body, specifically in cardiac valves and prosthetic joints. Since antibiotic use has both individual and societal side effects, especially when used repeatedly (as in antibiotic prophylaxis), multiple considerations face the dentist considering use of prophylactic antibiotics prior to dental therapy. This Quality Resource Guide, using an evidence-based approach, focuses on antibiotic prophylaxis in patients with cardiac valvular disease and with prosthetic joints. It discusses the rationale and implementation of guidelines derived by respected associations. Clear and easily referenced tables outline: Dental Procedures for Which Endocarditis Prophylaxis is Reasonable in High Risk Patients; Cardiac Conditions Associated with the Highest Risk of Adverse Outcome from Endocarditis for Which Antibiotic Prophylaxis before Dental Procedures is Reasonable; Antibiotic Regimens for a Dental Procedure; and Special Considerations for Selected Patients. The most recent guidance for use of prophylactic antibiotic therapy in patients with a prosthetic joint or other orthopedic implant is discussed, as well as the Appropriate Use Criteria (AUC) developed by the Academy of Oral and Maxillofacial Surgery. The QRG is an important reference for the dental clinician assessing a patient with cardiac or orthopedic considerations. It also provides background information for the dental office team to answer patients’ questions regarding prophylactic antibiotic therapy.