Polyethylene glycol (PEG) is a versatile polymer with overwhelming properties that enhance its abundant use in different applications. It is widely used in the food industry, various biomedical and pharmaceutical applications, and many daily used products such as cosmetics. In addition, PEGylation, the covalent binding of PEG molecules to nanocarriers, proteins, peptides, or drug molecules, has been designed as a brilliant approach to improve the pharmacokinetics and therapeutic efficacy of PEGylated therapeutics. The extensive application of PEGylation in the drug delivery field is reflected by the increasing number of commercially available PEGylated therapeutics approved through the last two decades and many others are under clinical trials for sooner approval. However, anti-PEG antibodies, both induced after the treatment with PEGylated therapeutics or naturally occurring in healthy individuals, were reported to negatively affect the pharmacokinetics and the therapeutic efficacy of the administered PEGylated therapeutics through the so-called accelerated blood clearance (ABC) phenomenon. Furthermore, hypersensitivity reactions (HSRs) have been reported in several cases following the administration of PEGylated therapeutics or other PEG-containing products. In addition, PEG nonbiodegradability, PEG degradation, and toxicity associated with polymerization reaction residues are remaining challenges. As a result, numerous polymers have been developed and investigated as potential alternatives for PEG in drug delivery and other medical and pharmaceutical applications.