Nanometric particles and crystals play very important roles in biological systems. For example, calcium orthophosphates (abbreviated as CaPO4) of nanometric dimensions represent the basic inorganic building blocks of bones and teeth of mammals. According to recent discoveries in biomineralization, zillions nanometric crystals of biologically formed CaPO4 are nucleated in body fluids and, afterwards, they are self-assembled into these complex structures. In addition, both a greater viability and a better proliferation of various types of cells have been detected on smaller crystals of CaPO4. All these effects are due to a higher surface-to-volume ratio, an increased reactivity and biomimetic morphologies of the nanometric particles. Thus, the nanometric and nanocrystalline forms of CaPO4 appear to be natural for living organisms and, thus, they have a great potential to revolutionize the hard tissue-engineering field, starting from bone repair and augmentation to controlled drug delivery systems. Therefore, preparation and applications of nanometric CaPO4 are the important topics in modern biomaterial science and such formulations have been already tested clinically for various purposes. Currently, more efforts are focused on the possibility of combining nanometric CaPO4 with cells, drugs and/or other biologically active substances for multipurpose applications. This review describes current state of the art and recent developments on the subject, starting from synthesis and characterization to biomedical and clinical applications.