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Bone tissue requires a range of complex mechanisms to allow the restoration of its structure and function. Bone healing is a signaling cascade process, involving cells secreting cytokines, growth factors, and pro-inflammatory factors in the defect site that will, subsequently, recruit surrounding stem cells to migrate, proliferate, and differentiate into bone-forming cells. Bioactive functional scaffolds could be applied to improve the bone healing processes where the organism is not able to fully regenerate the lost tissue. However, to be optimal, such scaffolds should act as osteoconductors - supporting bone-forming cells, providing nutrients, and sustaining the arrival of new blood vessels, and act as osteoinducers - slowly releasing signaling molecules that stimulate mesenchymal stem cells to differentiate and deposit mineralized bone matrix. Different compositions and shapes of scaffolds, cutting-edge technologies, application of signaling molecules to promote cell differentiation, and high-quality biomaterials are reaching favorable outcomes towards osteoblastic differentiation of stem cells in in vitro and in vivo researches for bone regeneration. Hydrogel-based biomaterials are being pointed as promising for bone tissue regeneration; however, despite all the research and high-impact scientific publications, there are still several challenges that prevent the use of hydrogel-based scaffolds for bone regeneration being feasible for their clinical application. Hence, the objective of this review is to consolidate and report, based on the current scientific literature, the approaches for bone tissue regeneration using bioactive hydrogel-based scaffolds, cell-based therapies, and three-dimensional bioprinting to define the key challenges preventing their use in clinical applications.