The major challenges faced by dental specialists today is in the assessment and management of patients with increasingly complex medical conditions, complex medical history and the use of multiple medications. Therefore, dental management in medically compromised patients requires special attention. Thorough knowledge about the pathophysiology of diseases, pharmacological action and their interactions with dental procedures is mandatory. The common medical conditions encountered by the dentist in daily practice include patients with cardiac diseases, pulmonary diseases, hypertension, diabetes, bleeding disorders, pregnant patients, patients with neurological disease, patients undergoing radiation therapy. Since medical complexity is often an indication for referral to a dental specialist, Endodontists should be prepared to accurately evaluate medically complex patients and identify situations that require a modification of normal treatment procedures and identify oral and systemic conditions requiring diagnosis and management.