Lipids are essential structural and functional components of cells. Little is known, however, about the evolution of lipid composition in different tissues. Here, we report a large-scale analysis of the lipidome evolution in six tissues of 32 species representing primates, rodents, and bats. While changes in genes' sequence and expression accumulate proportionally to the phylogenetic distances, <2% of the lipidome evolves this way. Yet, lipids constituting this 2% cluster in specific functions shared among all tissues. Among species, human show the largest amount of species-specific lipidome differences. Many of the uniquely human lipidome features localize in the brain cortex and cluster in specific pathways implicated in cognitive disorders.