Plasma membrane microdomains represent subcompartments of the plasma membrane characterized by a specific lipid and protein composition. The recognition of microdomains in nearly all the eukaryotic membranes has accredited them with specialized functions in health and disease. Several proteomic studies have recently addressed the specific composition of plasma membrane microdomains, and will be reviewed in this paper. Peculiar information has been obtained, but a comprehensive view of the main protein classes required to define the microdomain proteome is still missing. The achievement of this information is slowed by the difficulties encountered in resolving and analyzing hydrophobic proteins, but it could help in understanding the overall function of plasma membrane microdomains and their involvement in human pathology.