Abstract: Researchers in the developing field of regenerative medicine have identified bone tissue engineering as an attractive translational target. Clinical problems requiring bone regeneration are diverse and no single regeneration approach will likely resolve all injuries. Recent advances in the field of tissue engineering have included the use of sophisticated biocompatible scaffolds, new post-natal multipotent cell populations, and appropriate cellular stimulation for creation of an appropriate osteogenic microenvironment. Nell-1 [Nel-like molecule-1; Nel (a protein strongly expressed in neural tissue encoding epidermal growth factor like domain)], has been investigated for its ability to stimulate osteogenic differentiation and its potential to regenerate bone in vivo . Nell-1 is thought to specifically targets cells of the osteogenic lineage, thus reducing the possibility of adverse side effects in other tissues targeted by BMPs. Our long-term goal is to understand Nell-1 induced osteogenesis and provide a bone regeneration strategy that either replaces or enhances BMP induced bone regeneration. Nell-1's release from polymeric PLGA scaffolds with or without various coatings revealed that ionic interactions played a role in Nell-1's release, while hydroxyapatite provided an appropriate microenvironment to aid in Nell-1 induced bone regeneration. In vivo, Nell-1 was most retained on collagen coated scaffolds. Finally, Nell-1's ability to regulate ion transport was investigated in vitro. The data revealed that Nell-1 regulated inorganic phosphate (Pi) transport into cells resulting in accelerated mineralization. Neil-1's actions were mediated by the NaPi transporter, namely Pit-1 and Pit-2, activity directly and also increased Pit-2 production as early as 1 hour after stimulation. In conclusion, Nell-1 aids in bone regeneration by accelerating mineralization via increased Pi transport and increased extracellular matrix protein production. Future bone regeneration therapies will benefit from Nell-1's cellular specificity and osteogenic differentiation activities.