The chemotherapy agent L-asparaginase has been an important part of acute lymphoblastic leukemia therapy for over 30 years. Two of the main disadvantages of the drug are (1) the need for frequent intramuscular injection and (2) a very high rate of allergic reactions. Because of this, L-asparaginase seemed like an ideal target for pegylation and PEG-L-asparaginase was developed in the 1970s and 1980s. The drug has undergone extensive testing and appears to retain its antileukemic effectiveness while allowing less frequent administration than the native compound. While the actual cost to patients for PEG-L-asparaginase is greater than that of multiple injections of other L-asparaginases, the reduced need for physician visits and treatment of complications of therapy may make overall treatment costs considerably less than that of the conventional L-asparaginases. In the review below, we outline the history of therapy with L-asparaginase, the development of PEG-L-asparaginase, and clinical trials in which it has been administered.