Vertebrate skeletal differentiation retains elements from simpler phyla, and reflects the differentiation of supporting tissues programmed by primary embryonic development. This developmental scheme is driven by homeotic genes expressed in sequence, with subdivision of skeletal primordia driven by a combination of seven transmembrane-pass receptors responding to Wnt-family signals, and by bone morphogenetic family signals that define borders of individual bones. In sea-dwelling vertebrates, an essentially complete form of the skeleton adapted by the land-living vertebrates develops in cartilage, based on type II collagen and hydrophilic proteoglycans. In bony fishes, this skeleton is mineralized to form a solid bony skeleton. In the land-living vertebrates, most of the skeleton is replaced by an advanced vascular mineralized skeleton based on type I collagen, which reduces skeletal mass while facilitating use of skeletal mineral for metabolic homeostasis. Regulation of the mammalian skeleton, in this context, reflects practical adaptations to the needs for life on land that are related to ancestral developmental signals. This regulation includes central nervous system regulation that integrates bone turnover with overall metabolism. Recent work on skeletal development, in addition, demonstrates molecular mechanisms that cause developmental bone diseases.