Abstract Background Membrane-associated progesterone receptors (MAPRs) are thought to mediate a number of rapid cellular effects not involving changes in gene expression. They do not show sequence similarity to any of the classical steroid receptors. We were interested in identifying distant homologs of MAPR better to understand their biological roles. Results We have identified MAPRs as distant homologs of cytochrome b 5 . We have also found regions homologous to cytochrome b 5 in the mammalian HERC2 ubiquitin transferase proteins and a number of fungal chitin synthases. Conclusions In view of these findings, we propose that the heme-binding cytochrome b 5 domain served as a template for the evolution of membrane-associated binding pockets for non-heme ligands.