The expansion of mosquito-borne viral (arboviral) arthritis poses a significant threat to human health worldwide. Clinical reports show that arboviral arthritis can be persistent and debilitating, with evidence of bone pathology. As part of the Togaviridae family, alphaviruses are mosquito-borne viruses that are widely distributed throughout the globe causing extensive morbidity and mortality. Despite this, very little is known about the pathogenesis of disease caused by alphaviruses. It has been shown that macrophages play a crucial role in the development of alphaviral arthritis. Infection causes macrophage activation and the release of macrophage inhibitory factor (MIF), which subsequently plays a pivotal role in alphavirus-induced arthritis by regulating the expression of pro-inflammatory factors. This chapter discusses the role of the MIF-CD74 axis in the development of alphavirus arthritis and the therapeutic potential of antagonists in the treatment of alphaviral arthropathies.