Root canal therapy is the most efficient way to treat pulptitis and periapical inflammation, which can clear infections of root canal systems, fill the root canal firmly, and avoid reinfection. However, the variations in root canal morphology and complexity of infection confer difficulty in thoroughly eliminating microorganisms and their by-products in the root canal system, especially in the root apex area (including the top one-third of the root canal and periapical tissue), which is described as the hardest area to clean during endodontic treatment. Infection is difficult to remove entirely because the apex area is hard to approach using dental instruments and because of the existence of special morphological structures, such as apical ramification, intercanal anastomoses, and lateral branch of root canal. This review gives a brief introduction of the characteristics and difficulties of apical infection and knowledge on how to control such infections, including root apex preparation, irrigation and disinfection, and root canal filling.