With a steadily increasing prevalence, insulin resistance (IR) is a major public health issue. This syndrome is defined as a set of metabolic dysfunctions associated with, or contributing to, a range of serious health problems. These disorders include type 2 diabetes, metabolic syndrome, obesity, and non-alcoholic steatohepatitis (NASH). According to the literature in the field, several cell types like β-cell, myocyte, hepatocyte and/or adipocyte, as well as related complex signaling environment involved in peripheral insulin sensitivity are believed to be central in this pathology. Because of the central role of the liver in the whole-body energy homeostasis, liver insulin sensitivity and its potential relationship with mitochondrial oxidative phosphorylation appear to be crucial. The following short review highlights how liver mitochondria could be implicated in IR and should therefore be considered as a specific therapeutic target in the future.