OverviewNanoscience, where the properties of materials are exploited to innovative amazing applications, is involved in the size-dependent chemical and biological activity of bone substitute materials, which is indeed a fascinating field. The present chapter reviews the synthesis and chemical-physical characteristics of hydroxyapatite (HA) nano-crystals, which have excellent properties to represent an elective material covering a wide range of applications for bone substitution. We start from an examination of biogenic bone and tooth hydroxyapatite nanocrystals morphological and chemical-physical characteristics. The highlighted concepts have been used to review up-to date main new ideas on the preparation of synthetic apatitic bone substitutes mimicking the above biogenic properties, among which the nanosize is the basis of their self-assembly, self-mineralization and bone regeneration ability.Hydroxyapatite (HA) nanocrystals with high bioreabsorbability containing foreign ions and mimicking bone HA chemical-physical and physiological behaviour have been described. We have pointed to their possible use in preparing scaffolds with a porosity simulating that of spongy bone and upon which cells can be seeded, thereby developing ''in vitro autologous bone''. Biologically inspired HA nanocrystals/collagen composites have been reviewed, focusing on the role of a self-assembling strategy in conditioning the bone repairing activity of this biomaterial. Furthermore, considering that calcium phosphate/collagen composites are not limited to loading application, the possibility of preparing bio-inspired coating on the surface of metallic implants could be an advantageous approach.Finally, surface functionalization of HA nano-crystals with bioactive molecules makes them able to transfer information and to act selectively on the biological environment and can be considered one of the main future challenges for innovative bone substitute materials. 283 7.2