Hydrogels and nanogels have emerged as promising materials for biomedical applications owing to their large surface area and tunable mechanical and chemical properties. Their large surface area is well suited for bioconjugation, whilst the interior porous network can be utilized for the transport of valuable biomolecules. The use of biocompatible hydrophilic building blocks/linkers for the preparation of hydrogels and nanogels not only avoids undesired side effects within the biological system, but also retains high water content, thereby creating an environment which is very similar to extracellular matrix. Their tunable multivalency and hydrophilicity and excellent biocompatibility, together with ease of functionalization, makes polyglycerol macromonomers well suited for synthesizing cross-linked networks that can be used as extracellular matrix mimics. Here we provide an overview of the synthesis of polyglycerol-based hydrogels and nanogels for various biomedical applications.