Rheumatoid arthritis is one of the most prevalent autoimmune diseases at the present time, and it affects both sexes and is characterized by the incidence of women more than men about 1:3. Arthritis causes many negative effects in the various body systems, represented by the lymphatic, respiratory, muscular and blood systems, in addition to its effect on the heart, blood vessels and kidneys. Cytokines have an important role in stimulating the occurrence of rheumatoid arthritis, and these cytokines (IL-1, TNF-α, IL-8) attract inflammatory cells to the synovial membrane due to the erosion of bones and joints. Amethopterin, 4-amino 4-deoxy-N10-methylpteroyl-glutamic acid is a folate antagonist) developed more than 50 years ago in combination with several antifolate therapies used to fight malignant tumors. This review study Further elucidation of the mechanism of methotrexate to treat RA in the patients Methotrexate remains the mainstay of RA treatment and it important to identify the patients in whom the drug is effective and those in which toxicity may be an issue. Genetic and biomarkers may help to stratify patients and possibly shed light on the mechanism for efficacy and for toxicity of methotrexate for RA.