What types of genetic changes underlie evolution? Secreted signaling molecules (syn. ligands) can induce cells to switch states and thus largely contribute to the emergence of complex forms in multicellular organisms. It has been proposed that morphological evolution should preferentially involve changes in developmental toolkit genes such as signaling pathway components or transcription factors. However, this hypothesis has never been formally confronted to the bulk of accumulated experimental evidence. Here we examine the importance of ligandcoding genes for morphological evolution in animals. We use Gephebase (http:// www.gephebase.org), a database of genotype-phenotype relationships for evolutionary changes, and survey the genetic studies that mapped signaling genes as causative loci of morphological variation. To date, 19 signaling genes represent 20% of the cases where an animal morphological change has been mapped to a gene (80/391). This includes the signaling gene Agouti, which harbors multiple cis-regulatory alleles linked to color variation in vertebrates, contrasting with the effects of coding variation in its target, the melanocortin receptor MC1R. In sticklebacks, genetic mapping approaches have identified 4 signaling genes out of 14 loci associated with lake adaptations. Finally, in butterflies, a total of 18 allelic variants of the WntA Wnt-family ligand cause color pattern adaptations related to wing mimicry, both within and between species. We discuss possible hypotheses explaining these cases of natural replication (genetic parallelism) and conclude that signaling ligand loci are an important source of sequence variation underlying morphological change in nature.