Mitochondrial reactive oxygen species (mROS) have emerged as signaling molecules in physiology primarily as a result of studies of uncoupling mechanisms in mitochondrial respiration. The discovery that this mechanism negatively regulates mROS generation in many cell types has drawn the attention of the scientific community to the pathological consequences of excess mROS production. From reports of the energetic fluxes in cells grown under normal conditions, the hypothesis that mROS are an integrated physiological signal of the metabolic status of the cell has emerged. Here, we consider recent studies that support this point of view in two key nutrient sensors of the body, beta cells and the hypothalamus, which are the main coordinators of endocrine and nervous controls of energy metabolism and adipose tissue, which is of paramount importance in controlling body weight and, therefore, the development of obesity and type 2 diabetes. In this context, finely balanced mROS production may be at the core of proper metabolic maintenance, and unbalanced mROS production, which is largely documented, might be an important trigger of metabolic disorders.