More than half a century ago, an observation that folic acid antagonists interfere with the normal growth of cells led to the introduction, by Farber and colleagues of methotrexate (MTX) in the treatment regimen of children with acute lymphoblastic leukaemia1. Soon thereafter, MTX was reported to be effective in controlling disease activity both in patients with psoriatic arthritis and rheumatoid arthritis (RA) (2). MTX continues to be the most widely used disease-modifying antirheumatic drug (DMARD). Patients with these chronic conditions require prolonged and often life-long treatment. However, the drug is not without toxic effects, and 10 to 30 per cent of patients discontinue treatment due to side effects (3,4). Also, the dose of MTX required for effective control of disease activity varies among patients and the overall response rates vary between 35-65 per cent (5). Currently, no reliable tests are available to predict MTX efficacy or toxicity. In this issue, Ghodke et al (6) have reported single nucleotide polymorphisms (SNPs) across intracellular folate metabolic pathways in healthy Indian subjects. Folates are single carbon donors for the synthesis of purines, pyrimidines, and methionine and hence critical for DNA synthesis and cellular function. The genes they have looked at are involved in the intracellular transport (reduced folate carrier 1 or RFC1), and conversion ([gamma] glutamyl hydrolase or GGH) of methotrxate, metabolism of purine and pyrimidine (methylenetetrahydrofolate reductase or MTHFR, thymidylate synthase or TS, methionine synthase or MS, serine hydroxymethyltransferase I or SHMT 1 , aminoimidazol carboxamide ribinucleotide transformylase or ATIC, methionine synthase reductase or MTRR) and efflux of the drug (multidrug resistance protein 1 or MDR1). While MTX inhibits several of the folate-dependent enzymes, such as DHFR, ATIC, and TS resulting in cellular folate depletion, genetic variants in any of these genes can affect enzyme efficacy, and in turn, influence intracellular folate levels. What is the significance of the data reported by Ghatge et al (6)?