Purpose of Review Methotrexate (MTX) is the most widely used disease-modifying antirheumatic drug (DMARD) in paediatric rheumatology and the mainstay in the therapy of juvenile idiopathic arthritis (JIA). Despite its common use, about 30% of children fail to respond to this medicine that results in potentially irreversible joint damage. Recent Findings No clinical biomarker that would predict the outcome of MTX therapy exists. Results of several studies focused on gene polymorphisms and outcome of this DMARD therapy have been published, but no reliable genetic marker useful to tailor the therapy has been discovered so far. The results of the first genome-wide association study in this field have recently revealed new genetic candidates from outside the metabolic pathway of MTX that may be associated with the efficacy of treatment. Summary However promising, those outcomes need validation in independent prospective cohorts before we can claim that clinically useful biomarker predicting MTX treatment response is discovered.