The medaka, Oryzias latipes , a small egg-laying freshwater fish, is one of the three vertebrate model organisms in which genome-wide phenotype-driven mutant screens have been carried out. Despite a number of large-scale screens in zebrafish, a substantial number of mutants with new distinct phenotypes were identified in similar large-scale screens in the medaka. This observed difference in phenotype is due to the two species having a unique combination of genetic, biological and evolutional properties. The two genetic models share a whole-genome duplication event over that of tetrapods; however, each has independently specialized or lost the function of one of the two paralogues. The two fish species complement each other as genetic systems as straightforward comparison of phenotypes, ease of side-by-side analysis using the same techniques and simple and inexpensive husbandry of mutants make these small teleosts quite powerful in combination. Furthermore, both have draft genome sequences and bioinformatic tools available that facilitate further genetic dissection including whole-genome approaches. Together with the gene-driven approach to generate gene knockout mutants of the fish models, the two fish models complement the mouse in genetically dissecting vertebrate genome functions. The external embryogenesis and transparent embryos of the fish allow systematic isolation of embryonic lethal mutations, the most difficult targets in mammalian mutant screens. This chapter will describe how to work with both medaka and zebrafish almost as one species in a lab, focusing on medaka and highlighting the differences between the medaka and zebrafish systems.