High-dose methotrexate (HDMTX) is widely and safely used in oncology, with adequate measures including vigorous hydration, urine alkalinization and leucovorin rescue. Despite these precautions, some patients still develop HDMTX-induced nephrotoxicity, which leads to delayed methotrexate (MTX) clearance and sustained elevated plasma MTX levels, which can significantly increase MTX toxicity. Glucarpidase (carboxypeptidase G2, Voraxaseis a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, providing an alternate non-renal pathway for MTX elimination in patients with renal dysfunction during HDMTX treatment. Glucarpidase has recently been approved for the treatment of toxic plasma MTX concentrations in patients with delayed MTX clearance due to impaired renal function. Preclinical and clinical studies demonstrated good safety and efficacy in rapidly reducing elevated MTX levels. Further comparative studies are awaited to confirm the benefit of glucarpidase in terms of toxicity and survival.