Methotrexate (MTX) is one of the mainstays of treatment for several immune-mediated inflammatory joint and skin diseases, especially rheumatoid arthritis (RA) and moderate-to-severe psoriasis. Oral MTX has been used for the treatment of such diseases for decades for many reasons. There is, however, a relevant interpatient variability of clinical and safety outcomes that can also be related to differences in patients’ individual pharmacogenomic profile. Orally administered MTX has been found to have a saturable intestinal absorption and nonlinear pharmacokinetics, with significant consequences on drug bioavailability and clinical efficacy. The current evidence shows that parenterally administered MTX results in rapid and complete absorption, higher serum levels, and less variable exposure than oral dosing. The use of parenteral MTX, particularly when administered as a subcutaneous (SC) injection, has recently raised great interest in order to overcome the limitations of oral MTX. The effectiveness and safety of SC MTX have mostly been assessed in rheumatological settings, especially in patients with RA. There are only a limited number of data on SC MTX in juvenile idiopathic arthritis and even fewer in psoriatic disease. Various clinical experiences have suggested that SC MTX is more effective than oral MTX and may provide significant benefit even in patients in whom oral MTX proved to be inadequate. The increased efficacy of SC MTX resulting from higher drug exposure compared with oral MTX has been associated with a similar safety profile and in various reports even with a lower frequency of gastrointestinal complaints. The aim of this article was to review the available literature data on SC MTX treatment of inflammatory arthritis, with special emphasis on RA and psoriasis, examining differences with oral MTX treatment. A brief mention of pharmacokinetics, pharmacodynamic features and pharmacoeconomic considerations is also given.