Spine stereotactic body radiation therapy represents an important advancement in the management of spinal metastases that allows precise delivery of ablative doses of radiation therapy with excellent local control. Although the technique is being increasingly used in clinical practice, the optimal fractionation schedule remains uncertain. In this perspective paper, we review radiobiologic principles that support the use of multiple- versus single-fraction spine stereotactic body radiation therapy schedules and clinical data supporting the multiple-fraction approach. Specifically, we suggest that there may be a local control benefit of fractionation, while helping to limit the risk of toxicities such as vertebral body fracture, pain flare and radiation myelopathy. We conclude with future directions and the need for future study on this important topic.