Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. When left untreated, the disease can result in irreversible joint damage with high morbidity and mortality. Disease-modifying antirheumatic drugs are the cornerstones of treatment in RA. Disease-modifying antirheumatic drugs not only ameliorate the clinical signs and symptoms of disease, but also prevent the radiographic progression of joint damage. Methotrexate is one such disease-modifying antirheumatic drug that has been used in the treatment of RA for over two decades with excellent long-term efficacy and safety. However, there is significant variability in patients' response to methotrexate, both in terms of efficacy and toxicity. At the present time, there are no reliable means of predicting, a priori, an individual patient's response to methotrexate. In this review, recent published literature on the pharmacogenetics of methotrexate in RA is highlighted. Pharmacogenetics may be a powerful tool for optimizing methotrexate therapy in patients with RA.