Bone fusion represents a challenge in the orthopedics practice, being especially indicated for spine disorders. Spinal fusion can be defined as the bony union between two vertebral bodies obtained through the surgical introduction of an osteoconductive, osteoinductive, and osteogenic compound. Autogenous bone graft provides all these three qualities and is considered the gold standard. However, a high morbidity is associated with the harvest procedure. Intensive research efforts have been spent during the last decades to develop new approaches and technologies for successful spine fusion. In recent years, cell and gene therapies have attracted great interest from the scientific community. The improved knowledge of both mesenchymal stem cell biology and osteogenic molecules allowed their use in regenerative medicine, representing attractive approaches to achieve bone regeneration also in spinal surgery applications. In this review we aim to describe the developing gene- and cell-based bone regenerative approaches as promising future trends in spine fusion.