The centerpiece of the pathophysiologic mechanism of metabolic syndrome is insulin resistance. Recently, it is becoming evident that mitochondrial dysfunction is closely related to insulin resistance and metabolic syndrome. The underlying mechanism of mitochondrial dysfunction is very complex, which includes genetic factors from both nuclear and mitochondrial genome and numerous environmental factors. Several mitochondrial DNA polymorphisms are associated with the components of metabolic syndrome. Numerous chemicals and drugs may cause mitochondrial dysfunction and insulin resistance. Notably, it was recently reported that serum levels of several mitochondrial toxins, such as persistent organic pollutants are associated with metabolic syndrome, which necessitates further investigation to reveal its precise mechanism. Given that the health impact of metabolic syndrome is tremendous, it is necessary to develop therapeutic modalities to correct mitochondrial dysfunction or at least to halt its aggravation. In this regard, exercise can improve both mitochondrial function and insulin sensitivity, and some pharmaceutical agents were reported to improve mitochondrial function. However, further studies are warranted to find more effective therapeutic strategies to treat mitochondrial dysfunction. By doing so, we can also shed light on the path of research for other diseases related to mitochondrial dysfunction.