In order for regenerative medicine strategies to achieve desired outcomes, the materials employed, mostly consisting of combinations of stem cells, growth factors, and scaffolds, must possess the ability to augment the regeneration of the original tissue or serve as a replacement for damaged tissue, functioning in a manner similar to the natural tissue. Due to variations in regeneration capabilities among different tissues, certain tissues may just require biologics and biomaterials, while others with partial regenerative capabilities necessitate the presence of cells, biomolecules, and biomaterials for regeneration. The ECM is accountable for preserving the flexibility and structural integrity of tissues. The structure undergoes constant remodeling in response to changes in the local pH levels, growth factors, and receptor abundance. The extracellular matrix (ECM) of bone and cartilage is unique, as it specifically caters to the distinct functional needs of these tissues. Collagen is the primary constituent of all extracellular matrices (ECMs). The bone extracellular matrix is predominantly composed of collagenous proteins, accounting for 90% of its makeup. The remaining 10% consists of non-collagenous proteins. Osteoblasts are accountable for the production of these proteins, primarily involved in cellular adhesion. Hydroxyapatite is the primary inorganic constituent of hard tissues. Collagen provides a structural base that aids in the deposition of hydroxyapatite during the mineralization of tissues. The extracellular matrix (ECM) of bone can be categorized into two components: organic and mineral. Each entity has distinct and individual attributes. It is important to consider that materials intended for insertion into bone tissue should replicate these characteristics. This chapter presents a thorough overview of the extracellular matrix of bones.