Long bone non-unions represent a serious clinical and socioeconomical problem due to the prolonged episodes, frequent sequelae, and variable treatment effectiveness. Bone grafts, classically involving the autologous iliac crest graft as the 'gold standard' bone graft, enhance bone regeneration and fracture healing incorporating osteoconductive and/or osteoinductive/osteogenic capacity to the non-union under treatment. Structural alternatives to autologous bone grafts include allografts and bone substitutes, expanding the available stock but loosing biological properties associated with cells in the graft. Biological alternatives to autologous bone grafts include bone marrow concentration from iliac crest aspiration, bone marrow aspiration from reaming of the diaphyseal medullary canal in the long bones, and isolated, expanded mesenchymal stem cells under investigation. When the combination with natural and synthetic bone substitutes allows for larger volumes of structural grafts, the enhancement of the biological regenerative properties through the incorporation of cells and their secretoma permits to foresee new bone grafting solutions and techniques.