Administering asparaginase has always been problematic in adults since most general oncologists who treat adults are not familiar with its usage and toxicity. The toxicity profile of the drug is unique and not observed with any other chemotherapy agent. Furthermore, asparaginase is almost exclusively used in acute lymphoblastic leukemia (ALL) which is a very rare cancer in adults. Currently, the long acting pegylated form (pegasparaginase) is the only E. coli-derived asparaginase available in the US. The utilization of pediatric regimens is likely to lead to more adult patients receiving multiple doses of pegasparaginase. However, oncologists who treat adults may still be reluctant to use pegasparaginase or may unnecessarily discontinue its administration because of certain adverse effects. As a result, the clinical benefit of multiple doses of pegasparaginase will be missed. Despite the fact that pegasparaginase is associated with unique toxicities, the majority are non-fatal, manageable and reversible. Here, we describe real life cases of adults with ALL who were treated with pediatric-inspired regimens incorporating pegasparaginase to illustrate the management of several pegasparaginase-associated adverse effects and guide if and how to continue the drug.