In this review article, the state-of-the-art of calcium orthophosphate-based biocomposites and hybrid biomaterials suitable for biomedical applications is presented. This subject belongs to a rapidly expanding area of science and research, because these types of biomaterials offer many significant and exciting possibilities for hard tissue regeneration. Through the successful combinations of the desired properties of matrix materials with those of fillers (in such systems, calcium orthophosphates might play either role), innovative bone graft biomaterials can be designed. The review starts with an introduction to locate the reader. Further, general information on composites and hybrid materials including a brief description of their major constituents are presented. Various types of calcium orthophosphate-based bone-analogue biocomposites and hybrid biomaterials those are either already in use or being investigated for various biomedical applications are then extensively discussed. Many different formulations in terms of the material constituents, fabrication technologies, structural and bioactive properties, as well as both in vitro and in vivo characteristics have been already proposed. Among the others, the nano-structurally controlled biocomposites, those with nanosized calcium orthophosphates, biomimetically fabricated formulations with collagen, chitin and/or gelatin, as well as various functionally graded structures seem to be the most promising candidates for clinical applications. The specific advantages of using calcium orthophosphate-based biocomposites and hybrid biomaterials in the selected applications are highlighted. As the way from a laboratory to a hospital is a long one and the prospective biomedical candidates have to meet many different necessities, the review also examines the critical issues and scientific challenges that require further research and development.