The review article presents the main pathways for the synthesis of ceramides, their physiological role in the body. One of the factors in the development of insulin resistance is the increased synthesis of ceramides with a long acyl chain. Long-chain saturated non-esterified fatty acids (NEFA) are the main source of ceramide synthesis (palmitic is involved in the synthesis of ceramide C16: 0, stearic Cer-C18: 0, arachidonic Cer-C20: 0, and linoceric Cer-C24: 0). The increased content of the substrate (NEFA) contributes to their greater formation and accumulation of ceramides in the cell. Research has linked the development of insulin resistance to tumor necrosis factor alpha (TNF-α). In obesity, its expression is increased in adipose tissue, and it is able to induce insulin resistance. At the cellular level, TNF-alpha is a potent inhibitor of insulin-stimulated phosphorylation of tyrosine on the beta chain of the insulin receptor and insulin receptor substrate-1, which indicates a defect in the tyrosine kinase activity of the insulin receptor. Neutralizing TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of insulin receptor tyrosine kinase, especially in muscle and adipose tissue. Given the molecular mechanism for the development of insulin resistance and lipid-induced inflammation, ceramides or combinations of their panels in plasma can serve as biomarkers for identifying individuals at risk of developing type 2 diabetes mellitus and as potential targets for correcting insulin resistance and systemic inflammation.