The membrane-associated progesterone receptor (MAPR) protein family comprises of four members, progesterone receptor membrane component 1 (PGRMC) 1, PGRMC2, Neudesin, and Neuferricin/Cytochrome b5 domain containing 2 (CYB5D2), each with a conserved cytochrome b5-like heme-binding domain of ~100 amino acids. The heme-binding domain, which actually binds heme, is required for their activities. However,　the members differ greatly in their functions and action mechanisms. PGRMC1 is the original member of the family. PGRMC1 and PGRMC2 are membrane- bound proteins that are mainly located at the endoplasmic reticulum. In contrast, Neudesin and Neuferricin/CYB5D2 are secreted proteins. PGRMC1 and PGRMC2 were possibly generated from a common ancestral gene. However, Neudesin and Neuferricin/CYB5D2 are not evolutionarily related to the other members. PGRMC1 promotes cell survival and damage resistance in cancer cells. PGRMC1 and PGRMC2 are a target for therapeutic intervention in cancers and a potential biomarker of breast adenocarcinoma staging, respectively. PGRMC1 might play roles in lipid, drug, and hormone metabolism in the liver and neuroprotection in the brain. PGRMC2 might play roles in neuroendocrine functions in the brain. Neudesin promotes neural differentiation and proliferation in cultured neural precursor cells. Neudesin might also play a role in breast tumorigenesis. Neuferricin/CYB5D2 promotes neurogenesis and suppresses proliferation and survival in cultured neuronal cells. Neuferricin/ CYB5D2 also enhances cultured the survival of HeLa cells exposed to etoposide. Neudesin knockout mice are protected against high-fat diet-induced obesity, indicating that Neudesin plays roles in energy metabolism. However, as other knockout mice have not been reported, their physiological functions remain unclear.