A successful endodontic treatment depends on a comprehensive knowledge of the morphology of canal and its variations, an appropriate access cavity, cleaning and shaping, and adequate root canal filling. Lack of knowledge in this regard and missing a root canal are among the most common causes of failure of root canal treatments. Most previous studies on maxillary molars have reported that they usually have three roots and four canals since an extra canal is often found in the mesiobuccal root. Other anatomical variations, such as an extra C-shaped canal, have also been reported in distobuccal and palatal roots. Thus, because of having a more complex anatomy compared to other teeth, maxillary molars have the highest rate of endodontic failure. Several studies have assessed the morphology of root canal anatomy in different populations using different techniques such as sectioning, root canal clearing, association of a dental operating microscope and ultrasonic tips, periapical radiography, and computed tomography scanning. Recently, CBCT was suggested to three-dimensionally explore the root canal details before an endodontic treatment. The purpose of this chapter was to highlight the importance of having a thorough knowledge about the root canal morphology of the permanent first and second maxillary molar.