High doses of methotrexate are an important chemotherapy agent in the treatment of many childhood cancers. Treatment with HDMTX can cause unwanted side effects and induce many types of toxicity (e.g. Renal toxicity, liver toxicity, neurotoxicity, Hematologic toxicity, Pulmonary toxicity, gastrointestinal toxicity and Cutaneomucous toxicity) so adding leucovorin rescue provides the advantage of safe administration. However, HDMTX therapy should only be initiated when plasma methotrexate monitoring is available to determine adequacy of drug removal and risk of serious toxicity. Monitoring is an effective tool in managing the toxicity profile and guiding the dose of leucovorin. Sufficient hydration, urine alklinization, monitoring of liver and kidney functions and avoiding drugs interaction promote safe administration.