Obesity and Diabetes Mellitus (DM) are defined as worldwide pandemics by the World health organization due to their economic burden and widespread. Although a huge amount of research is being done in the field of obesity and DM today, many questions remain unsolved. Tissue inflammation is the main factor in the development of both obesity and DM, leading towards irreversible changes in the tissue and formation of specific complications. One of the widespread cytokines, tumor necrosis factor alpha (TNF-α), was shown to be involved with inflammation in the development of metabolic disorders and neurodegenerative diseases. Even though the role of TNF-α in the pathogenesis of these two diseases remains unclear, new ways of treating and preventing diseases based on TNF-α antagonism attracted the attention of scientists. In this review, TNF-α and its receptors’ structures and properties are explored, and their role in disease development, including obesity and type 2 DM (DM2) will be discussed by viewing data from literature.