Insulin resistance is characterised by hyperglycaemia, dyslipidaemia and oxidative stress prior to the development of type 2 diabetes mellitus. To date, a number of mechanisms have been proposed to link these syndromes together, but it remains unclear and obscure, what is a unifying condition that triggered these events in the progression of such metabolic disease. There has been a steady accumulation of data in numerous experimental studies showing the strong correlations between mitochondrial dysfunction, oxidative stress and insulin resistance. In addition, a growing number of studies suggests that the raised of plasma-free fatty acid level induced insulin resistance with the significant alteration of oxidative metabolism in various target tissues such as skeletal muscle, liver and adipose tissue. In this review, we herein propose the idea of long chain fatty acids induced mitochondrial dysfunctions as one of the greatest hallmark events in the pathophysiological development of insulin resistance and type 2 diabetes. The accumulation of reactive oxygen species (ROS), lipotoxicity, inflammation induced endoplasmic reticulum (ER) stress and alterations of mitochondrial gene subset expressions are the most detrimental occasions that lead to the developments of aberrant intracellular insulin signalling activity in a number of peripheral tissues, thus leading to insulin resistance and type 2 diabetes. This article is protected by copyright. All rights reserved.