Comparison of two related species is one of the most successful approaches to decipher general genetic principles in eukaryotes. This is best illustrated in yeast, where the model systems Saccharomyyces. cervisiae and Schizosaccharomyces. pombe have been examined. Powerful forward genetics in both species, species-specific differences in biological features and the phylogenetic distance between the two species, make them well suited for a comparative approach. Recent whole genome sequencing has also facilitated comparative genomics of these simple eukaryotes. It is now possible to go a step further using higher eukaryotes. A duplication of the genome at the base of the teleost radiation, facilitated evolution of almost 25,000 fish species, more than half of all vertebrate species together. Two teleost genetic model systems have emerged in the past few decades: zebrafish, in which large-scale mutagenesis has been successfully performed, and Medaka, a Japanese killifish with a century of history in genetics and now, as reported in this issue, many induced mutations. In this review we will illustrate how comparison of these two model species, Medaka and zebrafish, can reveal conserved and species-specific genetic and molecular mechanisms underlying vertebrate development.