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The role of mitochondria in the development of skeletal muscle insulin resistance has been an area of intense investigation and debate for over 20 years. The mitochondria is a multifaceted organelle that plays an integral part in substrate metabolism and cellular signalling. This article aims to summarize the current findings and thought regarding the relationship between mitochondria and insulin resistance in skeletal muscle.Skeletal muscle insulin resistance was earlier thought to result from deficiency in mitochondrial oxidative capacity and ectopic lipid accumulation. Recent evidence suggests that skeletal muscle insulin resistance in high-energy intake models (i.e. obesity) results primarily from disrupted mitochondrial bioenergetics and alterations in mitochondrial-associated cell signalling. These signalling pathways include reactive oxygen species and redox balance, fatty acid β-oxidation intermediates, mitochondrial derived peptides, sirtuins, microRNAs and novel nuclear-encoded, mitochondria-acting peptides.The pathophysiology of skeletal muscle insulin resistance is likely multifactorial involving many coordinated physiological processes. However, it is apparent that the mitochondria play an essential role in skeletal muscle insulin sensitivity in health, ageing and in numerous metabolic diseases. Deciphering the manifold functions of the mitochondria will allow us to understand the complex relationship between mitochondria and skeletal muscle insulin resistance.