Two sets of paired appendages are a characteristic feature of the body plan of jawed vertebrates. While the fossil record provides a good morphological description of limb evolution, the molecular mechanisms involved in this process are only now beginning to be understood. It is likely that the genes essential for limb development in modern vertebrates were also important players during limb evolution. In recent years, genes from a number of gene families have been described that play important roles both in limb induction and in later patterning processes. These advances facilitate inquiries into several important aspects of limb evolution such as their origin, position along the body axis, number and identity. Integrating paleontological, developmental and genetic data, we propose models to explain the evolution of paired appendages in vertebrates. Whereas previous syntheses have tended to focus on the roles of genes from a single gene family, most notably Hox genes, we emphasize the importance of considering the interactions among multiple genes from different gene families for understanding the evolution of complex developmental systems. Our models, which underscore the roles of gene duplication and regulatory 'tinkering', provide a conceptual framework for elucidating the evolution of serially homologous structures in general, and thus contribute to the burgeoning field seeking to uncover the genetic and developmental bases of evolution.