The purpose of this study is to outline relevant elements regarding the biochemical interactions between prosthetic materials used for obtaining implant-supported restorations and the oral environment. Implant-supported prostheses have seen unprecedented development in recent years, benefiting from the emergence of both new prosthetic materials (with increased biocompatibility and very good mechanical behavior), and computerized manufacturing technologies, which offer predictability, accuracy, and reproducibility. On the other hand, the quality of conventional materials for obtaining implant-supported prostheses is acknowledged, as they have already proven their clinical performance. The properties of PMMA (poly (methyl methacrylate))—which is a representative interim material frequently used in prosthodontics—and of PEEK (polyether ether ketone)—a biomaterial which is placed on the border between interim and final prosthetic use—are highlighted in order to illustrate the complex way these materials interact with the oral environment. In regard to definitive prosthetic materials used for obtaining implant-supported prostheses, emphasis is placed on zirconia-based ceramics. Zirconia exhibits several distinctive advantages (excellent aesthetics, good mechanical behavior, biocompatibility), through which its clinical applicability has become increasingly wide. Zirconia’s interaction with the oral environment (fibroblasts, osteoblasts, dental pulp cells, macrophages) is presented in a relevant synthesis, thus revealing its good biocompatibility.