Mucosal epithelia are at the interface with external environment actively interacting with the symbiotic microbiota, pathogens, antigens and chemicals. Epithelia play a crucial role in the regulation of mucosal immune cell responses, through different immune modulatory molecules. Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule and its role in immune tolerance has been well documented. Physiologic expression of HLA-G has been recently detected in different epithelial cells types as well as its ectopic expression has been observed in acute or chronic inflammatory diseases and carcinomas. In addition, HLA-G has been implicated in the proliferation and redifferentiation of human bronchial epithelial cells (HBEC) in vitro, in accordance with previous observation of other progenitor cells. An improved understanding of the role of HLA-G in the interaction between mucosal epithelia and the immune system and epithelial stem cells differentiation is important in the development of therapeutics aimed to manage diseases affecting epithelia.