The successful colonization of new environments is often achieved through adaptations or key innovations of existing physiological or biochemical mechanisms. The oxygen supply in marine invertebrates represent a complex and deeply integrated system which plays a fundamental role in animal adaptive plasticity. In particular, species which inhabit highly stochastic environments as shallow water or intertidal bands, have to cope with extremely different regimes of oxygen availability and effectively maintain a stable aerobic metabolism. Within this framework, we have focused on comparative physiology of Portunid Crabs hemocyanin, to evaluate the role molecular heterogeneity and functional plasticity of oxygen transport regulation. The analyses concerned the Mediterranean green crab Carcinus aestuarii, that inhabits shallow brackish waters with soft bottoms and mussel beds and two obligate aquatic species, the grey swimming crab Liocarcinus vernalis, that populates sandy bottoms from lower shore to a depth of -40 m, and the swimming crab L. depurator, distributed below the thermocline on fine sandy and muddy bottom. To assess the adaptive regulation of oxygen transport among these species, we have considered the effects that physiological and environmental modulators (lactate, pH and temperature) play on hemocyanin functioning. The biochemical parameters undergo to drastic changes during hypoxic events and show significant variations when animals move from aerobic to anaerobic metabolism. At molecular level we have verified that both lactate and pH play a central role in modulating the hemocyanin oxygen-binding properties and we have singled out the effect of each parameter on the oxygen affinity in resting and hypoxic conditions. From this study, a clear separation between subtidal and intertidal species emerges, evidencing the physiological plasticity that tolerant species exhibit when subjected to stressful conditions and underlying the importance that the oxygen availability has played in the actual ecological distribution. On the contrary, the hemocyanin of the three species does not manifest diverse sensitivities to the temperature effect, indicating a lower response to physical factors in these closely related species.