Abstract: Bioenergetics imbalance is a deleterious feature, which is present in the etiopathology of many human diseases, including in diabetes, cancer, and neurodegeneration. Therefore, targeting the components of mammalian bioenergetics, as well as the mechanisms that regulate the relationship between these components, could be a promising pharmacological strategy against a wide variety of pathologies. While for many years mammalian bioenergetics has been exclusively circumscribed to the mitochondrial oxidative phosphorylation (OXPHOS), which is the main mechanism to obtain adenosine triphosphate (ATP) in mammals, and to the cytoplasmic glycolysis and the closely related pentose phosphate pathway, in the last few decades many authors have advocated for expanding this term to include all the mechanisms that are involved in matching the cellular demands and production of energy to meet the needs of the cell under different states, including physiological and pathological conditions. This broader definition will include other key energy metabolites, such as the ubiquitous inorganic polyphosphate (polyP).