Rheumatoid arthritis (RA) is a chronic, systemic and progressive autoimmune disease of connective tissues common in middle age. Dysregulation of the tissue homeostasis involving inflammation is the hallmark of disease pathogenesis, inducing autoimmune insults that frequently lead to permanent disability. Although the advent of immunosuppressive and anti-inflammatory drugs and, more recently, pathogenic TNF-TNF-R axis-targeting biologics significantly delayed progressive joint destruction with significant reduction of disability and physical improvement, a large proportion of RA patients failed to respond to the treatment. In this regard, mesenchymal stem/stromal cells (MSC) are particularly attractive to the refractory patients to the pharmacologic intervention for their immunosuppressive/anti-inflammatory capacity as well as tissue reparative and/or regenerative potential. Local or systemic delivery of MSCs led to promising results in preclinical as well as in clinical studies of RA and thus proposing that these cells can be further exploited for their therapeutic application in RA and other degenerative connective tissue diseases. Mechanistically, paracrine factors appear to be the main contributors of MSC-mediated tissue regeneration in a number of preclinical and clinical studies rather than direct tissue cell replacement. More recently, extracellular vesicles (EVs) released from MSCs emerged as key paracrine messengers that can also participate in the healing process through influencing the local microenvironment with anti-inflammatory effects. It is highly likely that the use of these EVs becomes beneficial in the treatment of RA. Yet, identification of key components involved in the regenerative process needs to be assessed for developing efficient MSC-based strategy of RA treatment.