The fossil record is a unique repository of information on major morphological transitions. Increasingly, developmental, embryological, and functional genomic approaches have also conspired to reveal evolutionary trajectory of phenotypic shifts. Here, we use the vertebrate appendage to demonstrate how these disciplines can mutually reinforce each other to facilitate the generation and testing of hypotheses of morphological evolution. We discuss classical theories on the origins of paired fins, recent data on regulatory modulations of fish fins and tetrapod limbs, and case studies exploring the mechanisms of digit loss in tetrapods. We envision an era of research in which the deep history of morphological evolution can be revealed by integrating fossils of transitional forms with direct experimentation in the laboratory via genome manipulation, thereby shedding light on the relationship between genes, developmental processes, and the evolving phenotype.fossil record | development | genomics | evolution | limb P aleontologists in recent decades have discovered a host of new taxa that reveal transitional stages in the evolution of birds, whales, mammals, tetrapods, frogs, salamanders, and arthropods (1-9). This pulse of discovery is not an accident, but the result of an elaboration of our ability to identify likely sites for fossil recovery by using increasingly refined phylogenies, stratigraphic maps, and geological records. Likewise, imaging techniques, such as highenergy CT, have opened up old and understudied fossil collections as new vehicles for discovery. With advances in both fieldwork and imaging, the discovery of the phenotypic basis for morphological innovation is at a critical moment in its long history: Novel perspectives on classical questions of anatomical evolution are within our reach.Fossils, when placed in a phylogenetic context, can reveal taxa with novel combinations of characters that could not be predicted by studying extant creatures alone. If we lacked fossil evidence of mammal-like reptiles, for example, then the physiological and morphological similarities of birds and mammals would likely be interpreted as homologies rather than examples of parallel evolution (e.g., the discredited "Haemothermia" clade) (10, 11). In addition to identifying solid taxonomic groupings, these same fossils reveal transitional series in the origin of the mammalian dentition, ear, and cranium (3). Our understanding of numerous other transformations, from the origin of birds to the origin of tetrapods, is seriously limited without the knowledge of extinct stem taxa.A rich fossil record permits us to document robustly supported transformation series in the evolution of an anatomical feature, organ system, or body plan. However, to understand the pattern and process of evolutionary transitions, paleontologists have increasingly turned their attention to development. In recent years, the combination of technologies from developmental biology and abundant genomic resources for a multitude of model and nonmodel organ...