Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects, two problems associated with significant morbidity. The differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth factors. Neural EGF Like-Like molecule 1 (NELL-1) is a secreted glycoprotein that has proven, both in vitro and in vivo, to be a potent osteo-inductive factor. Furthermore, it has been shown to repress adipogenic differentiation and inflammation. NELL-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein (BMP) -2 and -9, and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of osteoporosis. Here we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.