Pathogenesis of type 2 diabetes mellitus (T2DM) and development of insulin resistance are characterized by multi‐stimuli factors notably glucolipotoxicity, generation of reactive oxygen species (ROS), epigenetic factors, activation of various transcriptional mediated pathways along with the augmented levels of various pro‐inflammatory cytokines. Among the various pro‐inflammatory cytokines, tumor necrosis factor‐alpha (TNF‐α) is one the most important pro‐inflammatory mediator that is critically involved in the development of insulin resistance and pathogenesis of T2DM. TNF‐α is mainly produced in adipocytes and/or peripheral tissues, and induces tissue‐specific inflammation through the involvement of generation of ROS and activation of various transcriptional mediated pathways. The raised level of TNF‐α induces insulin resistance in adipocytes and peripheral tissues by impairing the insulin signaling through serine phosphorylation that leads to the development of T2DM. Anti‐TNF‐α treatment strategies have been developed to reduce the incidence of insulin resistance and development of T2DM. In this article, we have briefly described how TNF‐α plays crucial role to induce insulin resistance and pathogenesis of T2DM. To block the inflammatory responses by blocking TNF‐α and TNF‐α signaling may be an effective strategy for the treatment of insulin resistance and T2DM. J. Cell. Biochem. 119: 105–110, 2018. © 2017 Wiley Periodicals, Inc.