The most common developmental disorder of the spine is scoliosis, a rotated, lateral deformity in the shape of the spinal column. Scoliosis may be part of the clinical spectrum that is observed in many developmental disorders, but typically presents as an isolated symptom in otherwise healthy adolescent children. Adolescent idiopathic scoliosis (AIS) has defied pathogenic understanding in part due to its genetic complexity, and to the lack of well-defined animal models. The disease is also remarkable in its sexual dimorphism, where girls are at more than five times greater risk of progressive deformity than boys. Breakthroughs have come from recent genome wide association studies (GWAS) and next generation sequencing (NGS) of human AIS cohorts. Post-hoc gene set and pathway-level analyses of genetic datasets have highlighted a role for cartilage biogenesis and the development of the intervertebral disc (IVD) in disease susceptibility. Moreover, next generation sequencing in AIS families, as well as modeling in vertebrate systems, has revealed that rare deficiencies in proteins of the cartilaginous extracellular matrix (ECM) collectively contribute to AIS. Thus, as in a jigsaw puzzle, the pieces coming together from multiple biologic studies suggest that deficiencies in the structural integrity and homeostasis of spinal cartilages are culprits in AIS susceptibility. Here, we update progress in understanding the genetic, biochemical, and cellular determinants of AIS. We also suggest a molecular model in which interaction of the hormonal environment with genetic susceptibility may increase risk of this common disorder of childhood.