The use of unmodified asparaginases (ASP) in the management of pediatric and adult acute lymphoblastic leukemia (ALL) is well established. Despite its well-proven clinical efficacy, the use of unmodified Escherichia coli ASP (EC-ASP) has been limited by frequent toxicities, especially the development of hypersensitivity reactions and neutralizing antibodies, and by the need for frequent administration. To overcome these limitations, EC-ASP enzyme was covalently linked to monomethoxypolyethylene glycol (PEG), forming the pegylated ASP (PEG-ASP) (Oncaspar). PEG-ASP has a prolonged half-life and is associated with decreased immunogenicity when compared with EC-ASP. Clinical trials have demonstrated the efficacy, safety and tolerability of PEG-ASP administered intramuscularly, subcutaneously or intravenously as part of multi-agent chemotherapy regimens in the management of newly diagnosed and relapsed pediatric and adult ALL. Here we discuss the pharmacology, pharmacokinetics, clinical trial results and potential side effects of PEG-ASP.