Variation in skeletal maturation is an important indicator of population health, but the exposure of healthy children to radiation has been approached with caution in recent years, resulting in few contemporary studies. Detailed longitudinal growth and skeletal maturity data have been collected from the largest, and longest-running birth cohort study in Africa, Birth to Twenty (Bt20). This study addresses variation in skeletal maturation in the unique context of rapid economic, social, and nutritional transition experienced in South Africa. The aims of this study were fourfold: (1) to describe the skeletal maturity of urban South African children; (2) to identify endogenous and exogenous factors responsible for advancement/delay in skeletal maturation; (3) to examine the relationship between skeletal maturation and pubertal development; and (4) to examine the evidence for a secular trend in skeletal maturity in South Africa.