Asparaginase is an important part of the remission induction regimen for treating acute lymphoblastic leukemia, the most common childhood cancer. The enzyme breaks down circulating asparagine and glutamine, creating a physiologically relevant model of amino acid deficiency. In leukemic cells which express very little asparagine synthetase (the enzyme that makes asparagine), asparaginase inflicts a lethal amino acid starvation. Yet for reasons not completely understood, cancer patients may unpredictably suffer severe complications, such as thromboembolism, liver failure and pancreatitis. Our lab was the first to report that phosphorylation of the translation factor, eIF2, by the amino acid sensor, GCN2, is activated by asparaginase. We were also the first to describe the ISR as the body’s first responder to asparaginase exposure. Since then we have gone on to show the impact of obesity and age on liver responses to asparaginase and we continue to use this agent as a research tool and study it to improve its efficacy to treat cancer and other diseases. This project utilizes a combination of biochemical, dietary, metabolic and molecular approaches in mice to identify mechanisms by which asparaginase causes metabolic complications and cell death. These results will be used to increase the safety and efficacy of asparaginase and to develop improved personalized approaches to the treatment of serious diseases.