Phenotypic variation within the skeleton has biological, behavioral, and biomedical functional implications for individuals and species. Thus, it is critical to understand how genomic, environmental, and mediating regulatory factors combine and interact to drive skeletal trait development and evolution. Recent research efforts to clarify these mechanisms have been made possible by expanded collections of genomic and phenotypic data from in vivo skeletal tissues, as well as the development of relevant in vitro skeletal cell culture systems. This review outlines this current work and recommends that continued exploration of this complexity should include an increased focus on how interactions between genomic and physiologically relevant contexts contribute to skeletal trait variation at population and evolutionary scales.