Previous research has shown that the lipid milieu surrounding membrane proteins may be an important factor in determining their activity. To investigate this we have examined sodium pump molecular activity and microsomal membrane lipid composition in the brain of five mammalian and eight avian species ranging in size from 30 g mice to 280 kg cattle and 13 g zebra finches to 35 kg emus, respectively. Sodium pump (Na+,K+-ATPase) activity was higher in the smaller species and showed a significant allometric decline with body mass in both the mammals (μmol Pi h-1 mg wet mass-1 = 6.2×mass-0.06) and birds (μmol Pi h-1 mg wet mass-1 = 5.4×mass-0.07). In small mammals, the elevated enzyme activity was related to allometric changes in both the concentration and the molecular activity (turnover rate) of sodium pumps, while in birds, no significant body-size-related variation was observed for either sodium pump concentration or molecular activity. Microsomal phospholipid fatty acid profile displayed little allometric variation in both the mammals and birds and was not correlated with molecular activity in either group. Brain phospholipids from both endothermic classes were dominated by the long chain n-3 polyunsaturate, docosahexaenoic acid [22:6 (n-3)], which accounted for an average of 28% and 34% of the total fatty acids in the mammals and birds respectively. Bird membranes also contained a relatively large percentage of 22:5 (n-6) as well as high levels of cholesterol. These results are discussed in relation to neurological function and the emerging field of membrane lipid rafts.