Methotrexate and TNF-blocking agents are the DMARDs most commonly prescribed for the treatment of rheumatoid arthritis (RA). However, not all patients treated with these nonbiologic and biologic DMARDs respond satisfactorily and few predictors of treatment efficacy have been identified, despite the fact that these therapies have now been available for many years. Many studies have investigated genetic factors that might predict patient responsiveness to therapies used to treat RA, and epigenetic studies regarding response to treatment are expected to accumulate in the literature in the near future. Herein, we review the advances in identifying genetic and epigenetic predictors of therapeutic responses to methotrexate and/or TNF inhibitors in RA that have been made to date, and highlight important considerations for future studies, such as the need for an improved, preferably biological, outcome measure reflecting response to treatment.