Mechanisms that affect thermal tolerance of ectothermic organisms have recently received much interest,mainly due to global warming and climate-change debates in both the public and in the scientific community.In physiological terms, thermal tolerance of several marine ectothermic taxa can be linked to oxygen availability,with capacity limitations in ventilatory and circulatory systems contributing to oxygen limitation at extremetemperatures. The present review briefly summarizes the processes that define thermal tolerance in a model cephalopodorganism, the cuttlefish Sepia officinalis, with a focus on the contribution of the cephalopod oxygen-carryingblood pigment, hemocyanin. When acutely exposed to either extremely high or low temperatures, cuttlefish displaya gradual transition to an anaerobic mode of energy production in key muscle tissues once critical temperatures (Tcrit)are reached. At high temperatures, stagnating metabolic rates and a developing hypoxemia can be correlated witha progressive failure of the circulatory system, well before Tcrit is reached. However, at low temperatures, decliningmetabolic rates cannot be related to ventilatory or circulatory failure. Rather, we propose a role for hemocyaninfunctional characteristics as a major limiting factor preventing proper tissue oxygenation. Using information onthe oxygen binding characteristics of cephalopod hemocyanins, we argue that high oxygen affinities (Πlow P50 values),as found at low temperatures, allow efficient oxygen shuttling only at very low venous oxygen partial pressures.Low venous PO2s limit rates of oxygen diffusion into cells, thus eventually causing the observed transition to anaerobicmetabolism. On the basis of existing blood physiological, molecular, and crystallographical data, the potentialto resolve the role of hemocyanin isoforms in thermal adaptation by an integrated molecular physiological approachis discussed