Successful endodontic practice requires complete knowledge about the various medical conditions and appropriateness in planning treatment as per the need with effective safety measures. This review focuses on a number of systemic complications encountered in endodontic practice that necessitate extra knowledge and care to prevent potential complications causing otherwise unnecessary morbidity and mortality. These include diabetes, multiple drug interactions, cardiac abnormalities, respiratory disorders and infectious diseases. When the procedure is carried out in healthy individuals, it is sufficient to concentration the technical course of action, but when there is a demand to preserve the tooth for patients with systemic illness and who are under medical management, it is equally important to avoid the potential medical emergencies. The first step in managing the patient with medical problems is acquiring a thorough health history, the second step is for the clinician to fully understand the significance of the disease. Each identified condition can affect dental care in a unique manner. Hence, practitioners must be aware of common diseases, and drugs that have an impact in endodontic treatment and the management options in medically compromised patients. This review aims to highlight the clinical conditions that require special endodontic attention.