Butyrophilins (BTN) belong to the immunoglobulin (Ig) superfamily of transmembrane proteins. These molecules are of increasing interest to immunologists, as they share a structural homology with B7 family members at the extracellular domain level. Moreover, a role of these molecules has been suggested in the negative regulation of lymphocyte activation for almost all the BTN that have been studied. In addition, the expression of some BTN family members has been reported to be associated with autoimmune diseases. Over the last few years, the number of BTN and BTN-like members has greatly increased. In this study, the butyrophilin family in mammals has been revisited, using phylogenetic analysis to identify all the family members and the phylogenetic relations among them, and to establish a standard nomenclature. Fourteen BTN groups were identified that are not all conserved between mammalian species. In addition, an overview of expression profiles and functional BTN data demonstrates that these molecules represent a new area of investigation for the design of future strategies in the modulation of the immune system.