Endodontic treatments are performed in pulpal inflammation conditions where local anesthesia is the most important pain control measure. But achieving local anesthesia in inflamed tissues is still a difficult process. Anatomical variations, inflammation & anxiety are the main factors responsible for anesthetic failure. The strategies for the management of the patient include; patient education, anxiety management, & pharmacological management to increase the success rate of local anesthesia. Other techniques include intraligamentary, intraosseous, intraseptal and intrapulpal injections to improve anesthesia, especially where conventional methods have failed. Each method has different efficacy and discomfort, and among them, intraosseous and intraligamentary injections have been found to be effective in enhancing the success of local anesthesia. This review explains the causes of local anesthetic failure and outlines the management to maximize patient’s comfort in endodontic treatment.