Epigenetic abnormalities are part of the pathogenetic alterations involved in the development of rheumatic disorders. In this context, the main musculoskeletal cell lineages, which are generated from the pool of mesenchymal stromal cells (MSCs), and the immune cells that participate in rheumatic diseases are deregulated. In this Review, we focus on microRNA (miRNA)-mediated regulatory pathways that control cell proliferation, drive the production of proinflammatory mediators and modulate bone remodelling. The main studies that identify miRNAs as regulators of immune cell fate, MSC differentiation and immunomodulatory properties — parameters that are altered in rheumatoid arthritis (RA) and osteoarthritis (OA) — are also discussed, with emphasis on the importance of miRNAs in the regulation of cellular machinery, extracellular matrix remodelling and cytokine release. A deeper understanding of the involvement of miRNAs in rheumatic diseases is needed before these regulatory pathways can be explored as therapeutic approaches for patients with RA or OA.