Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 
1980s and to this day is often the first line medication for RA treatment. In 
this review, we examine multiple hypotheses to explain the mechanism of 
methotrexate efficacy in RA. These include folate antagonism, adenosine 
signaling, generation of reactive oxygen species (ROS), decrease in adhesion 
molecules, alteration of cytokine profiles, and polyamine inhibition amongst 
some others. Currently, adenosine signaling is probably the most widely accepted 
explanation for the methotrexate mechanism in RA given that methotrexate 
increases adenosine levels and on engagement of adenosine with its extracellular 
receptors an intracellular cascade is activated promoting an overall 
anti-inflammatory state. In addition to these hypotheses, we examine the 
mechanism of methotrexate in RA from the perspective of its adverse effects and 
consider some of the newer genetic markers of methotrexate efficacy and toxicity 
in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the 
setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear 
explanation for the pathway and mechanism leading to methotrexate efficacy in 
RA, there may be a way to formulate more potent therapies with fewer side 
effects.