Multi-arm star poly(ethylene glycol) (PEG) polymers have a number of advantages over linear PEG polymers when used as carriers for drug delivery and controlled release. For instance, they have more terminals that can be modified to form multi-functional delivery systems with significantly increased drug loading. They can form micelles with higher stability and lower critical micelle concentration (CMC), which helps to improve the blood circulation and reduce the unfavorable burst drug release. Moreover, star PEG polymers can form three-dimensional hydrogels with controllable size and adjustable functions through cross-linking. Indeed, these unique advantages of star PEG polymers have promoted investigations on star PEG-based drug delivery systems. Herein, for the first time, we carefully reviewed the advances on the research and development of star PEG polymers, especially the 4-, 6- and 8-armed star PEG polymers, in delivery and controlled release of a series of bioactive agents, including both small molecules and biomacromolecules. Opportunities and challenges for successful translation of star PEG-based drug formulations into clinical use were also discussed. The upper panel shows the representative structures of star PEG derivatives. The lower panel shows three different dosage forms based on star PEG derivatives. Display omitted •Advantages of star PEG polymers as carriers for drug delivery were introduced.•Star PEG derivatives can be classified into conjugates, hydrogels and nanoparticles.•Small- and macro-molecules delivered by star PEG-based materials were reviewed.•Future directions for research on star PEG-based drug formulations were discussed.