Macrophage Migration Inhibitory Factor (MIF) is a critical cytokine implicated in various human disorders, with significant roles in innate and acquired immunity and inflammatory diseases. Recent investigations have linked MIF to the pathophysiology of cancer. Extensive research has been dedicated to studying its structure and actions, leading to its classification as both an enzyme and a hormone. Its isomerase enzymatic activity is exciting, which has sparked enthusiasm for developing specific small-molecule inhibitors targeting this unique enzymatic function to treat inflammatory illnesses potentially. While there is growing awareness of MIF’s importance in inflammation and cancer, the availability of adequate and extensively studied MIF inhibitors for relevant disease models remains limited. Advancing drug discovery necessitates the development of highly potent and selective small-molecule MIF inhibitors, along with rigorous validation in disease models. Our review article comprehensively summarizes recent progress recognizing MIF as a pharmaceutical target for inflammatory conditions and cancer. Furthermore, it highlights promising areas for future research in this domain and outlines recent advancements in identifying and designing small-molecule MIF inhibitors. These efforts aim to facilitate the development of novel therapies that target MIF and have the potential to address various disease conditions associated with its dysregulation. © 2024 Elsevier B.V., All rights reserved.