This chapter focuses on the ability of CO to act as a gasotransmitter, increase the mitochondrial function, and thus inhibit obesity and diabetes through the use of the heme oxygenase (HO)-1/CO/bilirubin pathway. The HO system attenuates the toxic effects of oxidative stress in obesity, metabolic syndrome, and cardiovascular disease. The epoxyeicosatrienoic acid-HO-1 pathway has been supported as one of the most potent targets for reversing the malignant effects of oxidative stress and pre-adipocyte differentiation resulting from diminished oxidative capacity in unbalanced mitochondrial dynamics. CO as a gasotransmitter is a potent regulator of vascular homeostasis while simultaneously increasing the insulin secretion. The antioxidant, anti-inflammatory, and anti-apoptotic properties of bilirubin and ferritin attenuate the mitochondrial reactive oxygen species (ROS) perturbations that elevate the oxidative stress, hypertension, and inflammatory adipokine signaling. Upregulation of HO-1-derived CO by PGC-1α further functions to hinder the proliferation of superoxide and restore the respiratory capacity by increasing the mitochondrial biogenesis and restoring the mtDNA integrity.