Progesterone receptor membrane component 1 (PGRMC1) contains a cytochrome b5 domain fold and belongs to the so-called membrane-associated progesterone receptor (MAPR) protein family that is widespread in eukaryotes. PGRMC1 and the related PGRMC2 mammalian family member diverged sometime after the evolution of segmented metazoan body plan and the appearance of vertebrates. Therefore PGRMC1 might be expected to be involved in some ancient eukaryotic processes, as well as more modern functions related to multicellularity and tissue interactions. Perhaps this explains the perplexing diversity of contexts where PGRMC1 has been observed, apparently being involved in different cellular processes at various sub-cellular locations. This review attempts to collate and interpret these observations. Ironically, despite being the archetypal member of the MAPR family, it has yet to be demonstrated that PGRMC1 exhibits specific progesterone binding. Potential roles of heme and steroid/sterol ligands are reviewed, as well as the implications of apparent target sequences within PGRMC1 for binding by SH2- and SH3-domain proteins as well as kinases. These motifs are modelled using the cytochrome b5 domain NMR structure of the Arabidopsis protein 1J03, implicating a possible function for PGRMC1 as an adaptor protein involved in regulating protein interactions and intracellular signal transduction and/or membrane trafficking. This interpretation is supported by the apparent presence of immunoreceptor tyrosine-based activation motif/ITAM sequences that are involved in endocytosis and vesicle targeting, and the colocalisation of PGRMC1 with caveolin and at the cytoplasmic membrane. Evidence for roles in disease, especially cancer, is also discussed.