Nano-sized particles and crystals play an important role in the formation of calcified tissues of various animals. For example, nano-sized and nanocrystalline calcium orthophosphates in the form of apatites of biological origin represent the basic inorganic building blocks of bones and teeth of mammals. Namely, according the recent developments in biomineralization, tens to hundreds nanodimensional crystals of a biological apatite are self-assembled into these complex structures. This process occurs under a strict control by bioorganic matrixes. Furthermore, both a greater viability and a better proliferation of various types of cells have been detected on smaller crystals of calcium orthophosphates. Thus, the nano-sized and nanocrystalline forms of calcium orthophosphates have a great potential to revolutionize the hard tissue-engineering field, starting from bone repair and augmentation to controlled drug delivery systems. This review reports on current state of the art and recent developments on the subject, starting from synthesis and characterization to biomedical and clinical applications. Furthermore, the review also discusses possible directions for future research and development.