Background: Although millions of root canal treatments are performed globally on a daily basis, factors that determine the number of main root canals in a tooth have not yet been elucidated. Variations in the number of root canals in different teeth is of utmost importance in clinical practice. However, clinicians aren´t aware about the determinants of such number, let alone these determinants have been approached in the literature, to the best of our knowledge. Purpose: This narrative review aimed to integrate the potential mechanisms involved in determining the number of main canals in a permanent tooth. Methods: We used the search terms “root canal number,” “root canal morphology,” “tooth morphology,” “root development,” and “root formation” to identify articles from the PubMed and Scopus databases. Results: 57 articles and 2 books were obtained. A multifactorial basis is plausible considering the influence of anthropological, demographic, environmental, genetic, epigenetic, tooth size related mechanisms and the pivotal role of Hertwig’s epithelial root sheath. Live-cell imaging techniques, mathematical models, quantitative genetics and dental phenomics could provide insightful information in the near future. Conclusions: Overall, it seems that the potential mechanisms determining the number of main canals in a tooth have a multifactorial basis. The orchestrating role of the Hertwig's epithelial root sheath seems pivotal, although the specific regulatory signals that induce or repress its diaphragmatic processes remain unknown. However, there is a dire need for molecular studies that help unveil these and other potential mechanisms involved.