Methotrexate (MTX) remains a mainstay in the treatment of children with hematological malignancies. The availability of an antidote/rescue agent, leucovorin (LV) has allowed escalation of MTX doses to achieve enormous plasma concentrations, compared with plasma folate. However, a recent review of more than 40 trials for children with ALL concluded that the addition of high dose MTX (HDMTX) in many different doses and schedules did not improve CNS therapy and made only minor improvements in systemic therapy for children with ALL . Some assessment suggested that by HDMTX benefits only limited amount of children with ALL. Recent treatment schedules vary markedly in terms of timing, dosing and scheduling of MTX and/or leukovorin, which may leave us uncertain with ideas such as "how should we best use HDMTX and LV?" or "why are we still using such by industry recommended doses of MTX?" The answer of how best to incorporate HDMTX and/or LV into ALL treatment plans is still not known and further clinical and pharmacological studies dealing with still controversial systemic MTX issue are actual even now, after more than 5 decades of clinical experiences with the MTX in pediatric oncology.