Apolipoprotein M (ApoM) is a novel lipoprotein-associated plasma protein of the apolipoprotein family. It is predominantly enriched in high-density lipoprotein (HDL), and is also present in small quantities in low-density lipoprotein (LDL) and in very low-density lipoprotein. Transgenic animal experiments have suggested that ApoM can be transformed into various lipoproteins and may be involved in lipoprotein metabolism. ApoM has five subtypes, however, their biological functions remain to be elucidated. The α-helix, formed by ApoM through hydrophobic signal peptides, is anchored to the phospholipid monomolecular layers of HDL. Hydrophobic domains can associate with small lipophilic ligands and perform biological functions. ApoM may affect HDL metabolism and exhibit anti-atherosclerotic functions. Human HDL, containing ApoM subfractions, can protect LDL from oxidation and regulate cholesterol efflux more effectively than HDL without ApoM. Therefore, it is highly correlated with plasma cholesterol levels in the human body. Although previous studies have reported no difference in ApoM between groups of patients with coronary heart disease (CHD) and a normal control groups, the anti-atherosclerotic effect of ApoM is evident. ApoM is highly expressed in renal proximal tubule cells and is secreted into the urine in tubule cells. However, it is usually reabsorbed by giantin-associated proteins in a process, which is also affected in kidney disease. In addition to liver and kidney cells, low expression levels of ApoM occur in the intestinal tract and are associated with lymph node metastasis of colorectal cancer. ApoM gene polymorphism is associated with CHD, diabetes and other immune-associated diseases. Investigations into the gene regulation of ApoM may assist in further clarifying the role of ApoM in blood glucose and lipid metabolism. Genetic modification of the mouse ApoM gene is an essential technique to investigate the gene expression and regulation of ApoM, and to clarify the potential roles of ApoM in lipoprotein metabolism, atherosclerosis, diabetes and renal diseases.