The human leukocyte antigen (HLA)-G non-classical major histocompatibility complex (MHC) class I molecule was originally described in first-trimester trophoblasts at the fetal–maternal interface in 1990. Eight years later, the First International Conference on this molecule was inaugurated by Prof Jean Dausset, recipient of the Nobel Prize in Medicine. The Fifth International Conference on HLA-G, held in Paris on July 2009, began with a tribute to Prof Jean Dausset who left us recently. This conference was co-chaired by Dr Edgardo D. Carosella and Prof Hans Grosse-Wilde, included 57 oral presentations and was attended by approximately 140 delegates from 16 countries. We summarize here the major advances on the HLA-G molecule that were reported, including findings on its biological activity and characterization of new mechanisms of action, notably through mesenchymal stem cells and regulatory cells, and the previously unexplored role of HLA-G on immune cells such as γδ T-cells and B lymphocytes. Furthermore, the role of HLA-G during pregnancy was revisited and its impact in pathologies such as cancer, autoimmune disorders and transplantation was further extended.