Recent observations indicate that the cross-sectional area (CSA) of vertebral bodies are on average 10% smaller in healthy newborn girls than in newborn boys - a striking difference that increases during infancy and puberty, and is greatest by the time of sexual and skeletal maturity. The smaller vertebral CSA in females is associated with greater spinal flexibility, and could represent the human adaptation to fetal load in bipedal posture. Unfortunately, it also imparts a mechanical disadvantage that increases stress within the vertebrae for all physical activities. This review summarizes the potential endocrine, genetic, and environmental determinants of vertebral cross-sectional growth and current knowledge on the association between the small female vertebrae and increased risk for a broad array of spinal conditions across the lifespan. Copyright © 2018 Endocrine Society.