Root canal anatomy may present clinicians with a complex clinical challenge that requires diagnostic approaches, access modification, and clinical skills to successfully localize, negotiate, disinfect, and seal the root canal system. This article discusses the clinical implications of endodontic therapy on permanent mandibular first molars. The number of roots on the mandibular first molar is directly related to ethnicity. Canal morphology has a significant effect on treatment protocol: Mesial roots present two canals on a regular basis, adopting 2-2 and 2-1 as the most common configurations. A third canal is present in 2.6% of the population. The most common configuration in the distal root is type I (62.7%), followed by type II (14.5%) and type IV (12.4%). Diagnosis and treatment of complex root canal systems often require specialized training that may be beyond the scope of the average general practitioner. Access modifications are required to find extra roots and/or canals. The instrumentation of the third root requires a different access and small, flexible instruments, given the curvature that is usually present buccally in the apical third. The incidence of isthmuses is 55% in the mesial root and 20% in the distal root. This anatomical configuration should be taken into consideration during endodontic treatment as well as during periapical surgery.