In the 1970s, morphological evidence collected by electron microscopy linked mineral deposition ("calcification" or "mineralization") in newly-forming bone to membrane-encapsulated particles of a diameter of approximately 100 nm (50-200 nm) that were called "matrix vesicles". As the characterisation of these vesicles progressed towards their biochemical composition, the role of lipids in the biomineralization process appeared to be crucial. In particular, a group of cell-membrane phospholipids were identified as major players in the crystal formation process. Indeed, in the 1980s it became clear that phosphatidylserine, together with proteins of the annexin family, was among the most important molecules in binding calcium ions and that this phospholipid was involved in the regulation of the early stages of mineralization in vivo. During the same period of time, the number of surgical implantations of orthopaedic, dental and maxilo-facial devices requiring full integration with the treated bone prompted the study of new functionalization molecules able to establish a stable bonding with the mineral phase of the host tissue. In the late 1990 s studies started that aimed at exploiting the potential of calcium-binding phospholipids and, in particular, of the phosphatidylserine as functionalization molecules to improve the osteointegration of artificial implants. Later, papers have been published that show the potential of the phophatidylserine and phosphatidylserine-mimicking coating technology to promote calcification both in vitro and in vivo. The promising results support the future clinical application of these novel osteointegrative biomaterials.