At present the diabetes mellitus (DM) constitutes a tremendous sanitary problem with values of morbility, prevalence and economical costs highly elevated, mainly because type 2 DM. These facts have stimulated the scientific research on the processes of glucolipotoxicity and of insulin resistance and their contribution to the development of type 2 DM. Both hyperglycemia and hyperlipidemia are important biochemical alterations in the DM that produce toxic effects. Chronic hyperglycemia predisposes to the micro and macrovascular complications of DM through the glucoadaptation, glucotoxicity and glucoapoptosis steps, in which the alterations of the hexosamine pathway, glycation of key proteins on the insulin action cascade and oxidative stress of beta-cells produce a decrease in the synthesis and secretion of insulin together with resistance to this hormone. Also, the lipotoxic process is preceded by a lipoadaptation period characterized by the induction of genic programs directed to eliminate the excess of lipid metabolites through the activation of lipolitic routes and inhibition of lipogenesis. Nevertheless the persistence of hyperlipidemia produced a lipotoxicity facilitates the apparition of lipoapoptosis in which ceramides and nitric oxide play a role. Glucolipotoxicity concept was proposed by Prentki and Corkey in order to explain the metabolic alterations present in type 2 DM associated to obesity, such as increased abdominal fat, insulin resistance and abnormal insulin secretion. It is known that insulin resistance play an important role in the development of type 2 DM, until the point that it is already present 10 to 20 years before type 2 DM starts and it is a good predictor of this nosologic entity. Accordingly, a better knowledge of the mechanisms implied on insulin resistance may be very useful for the future treatment of patients with type 2 DM, which is considered as one of the great epidemics of the XXI century.