Polyphosphoesters (PPEs) with repeating phosphoester bonds in the backbone are structurally versatile, biocompatible, and biodegradable through hydrolysis as well as enzymatic digestion under physiological conditions. They are appealing for biological applications because of their potential functionality, biocompatibility, and similarity to biomacromolecules such as nucleic acids. The expanding scope of PPEs in materials science, especially as biomaterials, is described in this review. We mainly focus on controlled synthetic methods of PPEs, which provide access to novel and complex polymer structures, especially for block copolymers. The hydrolytic and enzymatic degradation of PPEs, thermoresponsive PPEs, and biomedical applications have also been discussed.