Rheumatoid Arthritis is one of the most common autoimmune diseases, causing irreversible joint damage and disability. Methotrexate (MTX) is the gold standard drug for this. The low cost, easy availability and high efficacy makes it the most important and commonly used DMARD in developing and low income countries. However, long term use of MTX is also associated with intolerance including gastrointestinal effects such as nausea, vomiting, abdominal pain and diarrhoea. In addition, anticipatory, associative and behavioural symptoms such as anxiety and irritability are also observed. These adverse effects arise as a conditioned response and are often inadequately managed, leading to discontinuation of treatment. Understanding and assessing the incidence of MTX intolerance across ethnicities and geographical regions would lead to a better treatment compliance. In this review we present a compilation of the available literature on Methotrexate intolerance in Rheumatoid Arthritis and strategies to mitigate this effect.