PEGylation, the process of coating nanoparticles with polyethylene glycol (PEG), is a widely used strategy to enhance the efficiency of drug and gene delivery to target cells and tissues. This approach, inspired by the success of PEGylating proteins to improve systemic circulation time and reduce immunogenicity, has been extensively studied for its impact on the fate of systemically administered nanoparticle formulations. PEG coatings on nanoparticles shield their surfaces from aggregation, opsonization, and phagocytosis, thereby prolonging systemic circulation time. The article reviews the history of PEGylated nanoparticle formulations, including the factors that influence circulation time, such as PEG molecular weight, surface density, and nanoparticle core properties. It also discusses how PEG coatings have been utilized to overcome biological barriers associated with various modes of administration, from gastrointestinal to ocular delivery. Additionally, the article covers methods for PEGylating nanoparticles and characterizing PEG surface density, which is crucial for improving drug and gene delivery. The benefits of PEGylation in reducing systemic toxicity and immunogenicity are also explored, along with potential alternatives to PEG and non-systemic applications of PEGylated nanoparticles.PEGylation, the process of coating nanoparticles with polyethylene glycol (PEG), is a widely used strategy to enhance the efficiency of drug and gene delivery to target cells and tissues. This approach, inspired by the success of PEGylating proteins to improve systemic circulation time and reduce immunogenicity, has been extensively studied for its impact on the fate of systemically administered nanoparticle formulations. PEG coatings on nanoparticles shield their surfaces from aggregation, opsonization, and phagocytosis, thereby prolonging systemic circulation time. The article reviews the history of PEGylated nanoparticle formulations, including the factors that influence circulation time, such as PEG molecular weight, surface density, and nanoparticle core properties. It also discusses how PEG coatings have been utilized to overcome biological barriers associated with various modes of administration, from gastrointestinal to ocular delivery. Additionally, the article covers methods for PEGylating nanoparticles and characterizing PEG surface density, which is crucial for improving drug and gene delivery. The benefits of PEGylation in reducing systemic toxicity and immunogenicity are also explored, along with potential alternatives to PEG and non-systemic applications of PEGylated nanoparticles.