Systemic inflammatory and autoimmune diseases and myelodysplastic syndromes have been linked in individual patients and in larger case series for at least 25 years. These associations frequently include thyroid disease, neutrophilic dermatoses, polyarthritis, connective tissue diseases, vasculitis, and autoimmune cytopenias. Studies have found that autoimmune disease (or its therapy) is a risk factor for the development of myelodysplastic syndromes, but such syndromes might also be an instigator of autoimmune disease. Epidemiological studies examining disease risk in myelodysplastic syndromes with and without comorbid autoimmune illness have reached mixed conclusions. The pathophysiology of myelodysplastic syndromes is tightly linked to excessive inflammatory activity in the bone marrow microenvironment, which could promote systemic inflammatory and autoimmune diseases directly or by stimulation of the adaptive immune response. Alternatively, autoimmune diseases could promote clonal evolution and disordered bone marrow growth, promoting the development of myeloid malignancy. Additionally, therapy-related myeloid neoplasms-including myelodysplastic syndromes-have been diagnosed after treatment of autoimmune diseases with immunosuppressant therapies. These associations raise the following question: are myelodysplastic syndromes and systemic inflammatory and autoimmune diseases two sides of the same coin-that is, do they share an underlying disease state that can manifest as a myeloid neoplasm, an autoinflammatory illness, or both? VEXAS syndrome, which was first reported in 2020, is caused by a mutation that affects myeloid-restricted cells and manifests with both myelodysplasia and autoinflammation, and could give insight into this biological possibility. We note that systemic inflammatory and autoimmune diseases are often steroid-dependent; however, studies have also evaluated the roles of other immunomodulating therapies. In this Viewpoint, we critically appraise and review the literature on the epidemiology, pathophysiology, and management of systemic inflammatory and autoimmune diseases that are associated with myelodysplastic syndromes and related diseases.