Considering the variety of species that depend on hemoglobin for oxygen transport, these molecules must execute their primary function under extreme environmental conditions. Hence, a thermodynamic analysis of oxygen binding with hemoglobins from different species reveals a series of adaptive mechanisms which are based on the thermodynamic connection between the binding of heterotropic effectors and the reaction with oxygen.The examples reported, from fishes to human fetus, illustrate how evolution can alter the structural basis of the heterotropic interactions to optimize the oxygenation-deoxygenation cycle in dependence of the physiological needs of the particular organisms. Moreover they show that a thermodynamic analysis of the reaction with oxygen overcomes the meaning of a detailed structural and functional characterization going deeper into the physiology of the specific organism.Respiratory pigments directly link external conditions with body requirements and are therefore interesting systems for studying the effect of the environment on molecular evolution. Considering the variety of species that depend on hemoglobin for oxygen transport, these molecules must execute their primary function under extreme environmental conditions. Hence, the hemoglobins have experienced a major evolutionary pressure which has led to the development of a number of complex regulatory mechanisms operative at the molecular level and designed to fulfil the physiological requirements of a given species.All vertebrate hemoglobins exhibit a marked degree of cooperativity between subunits or 'heme-heme' interaction (homotropic interactions) which enables maximum oxygen unloading at relatively high oxygen tension. In the simple model, cooperativity in oxygen binding is achieved through the conformational transition, between the deoxy-low-affinity state (or T state) and the oxy-high-affinity state (or R state), which accounts for the sigmoidal shape of the oxygen binding curve. In addition, the oxygen affinity of hemoglobin is affected by several metabolic effectors (heterotropic interactions) such as chloride, protons (Bohr effect), CO, and organic phosphates. Under physiological conditions, in fact, all these effectors bind preferentially to the deoxy conformation (T state) of hemoglobin thereby shifting the allosteric Correspondence to B . Giardina, Istituto di Chimica, Universith Cattolica del "Sacro Cuore", Largo F. equilibrium ( T o R ) towards the T state and lowering the overall 0, affinity of the molecule. The modulation of function induced by these effectors has important physiological effects. For example, at the level of respiring tissues, the decrease of 0, affinity brought about by the increase in proton activity (alkaline Bohr effect) allows a more efficient unloading of 0, and contributes to the neutralization of protons produced by CO, and lactic acid.Another important feature of the reaction of hemoproteins with 0, is its temperature dependence which is governed by the associated overall enthalpy change (AH). Oxyge...