In modern societies, decreased physical activity, nutritional transition and aging contribute to the increase in the prevalence of obesity and its associated pathologies (as cardiovascular diseases and type 2 diabetes). Obesity is tightly correlated with insulin resistance, which appears in the early stages of type 2 diabetes. As skeletal muscle is quantitatively the main tissue involved in glucose transport in response to insulin, muscle insulin resistance is a key step in the etiology of type 2 diabetes. Several alterations of skeletal muscle insulin signaling in various models of obesity or type 2 diabetes have been evidenced and numerous underlying mechanisms have been hypothesized. Among them, muscle lipotoxicity, obesity-induced adipose tissue inflammation and oxidative stress following excess of energetic substrates could be involved, independently or synergically, in the development of muscle insulin resistance. Moreover, mitochondrial alterations have been reported in the skeletal muscle of obese or diabetic patients and animals. This suggests that mitochondrion, through its capacity of regulating cellular fatty acids flux and redox state, may play a key role in obesity-induced skeletal muscle insulin resistance. (C) 2011 Elsevier Masson SAS. All rights reserved.