The success of endodontic therapy depends on achieving three-dimensional obturation of the root canal system by forming a hermetic seal that blocks all portals of entry between the tooth and the periodontium. Obturation is achieved mainly through two components: a root canal sealer and a core filling obturation material. As most of the core filling materials used today are non-adhesive, it is the root canal sealer that plays an important role in achieving an airtight seal throughout the canal, including the apical foramen, canal irregularities, and minor discrepancies between the dentinal wall of the canal and the core. The advent of MTA-based sealers, a tricalcium silicate-based cement, has provided a new category of sealers with superior sealing ability and biocompatibility, thereby providing a biological seal. This review article will shed light on the evolution of MTA-based sealers and their revolutionary applications in endodontic therapy.