Innovations in digital manufacturing enabled the fabrication of implant-supported fixed dental prostheses (ISFDPs) in a wide variety of recently introduced materials. Computer-aided design and computer-aided manufacturing (CAD-CAM) milling allows the fabrication of ISFDPs with high accuracy by reducing the fabrication steps of large-span frameworks. The longevity of ISFDPs depends on the overall mechanical properties of the framework material including its fit, and the physical properties of the veneering material and its bond with the framework. This comprehensive review summarizes the recent information on millable CAD-CAM framework materials such as pre-sintered soft alloys, fiber-reinforced composite resins, PEEK, and PEKK in high-performance polymer family, and 4Y-TZP. Even though promising results have been obtained with the use of new generation millable CAD-CAM materials for ISFDPs, clinical studies are lacking and future research should focus on the overall performance of these millable materials in both static and dynamic conditions.