Comparing two complementary species is a promising approach to broadening our understanding of disease simulation. Zebrafish and medaka are the top two fish models in biomedical research and their soaring profiles in the last three decades are compelling. Although there are far more studies using the zebrafish model than medaka in the literature, the two systems are comparable and complementary to each other. Despite the similarities, there are few anatomic and transcriptomic differences between the two species. The successful genome sequencing of medaka and zebrafish has shown that fishes and higher animals are identical in terms of genetic composition. Approximately 20,000 genes in medaka are nearly the same as that of humans with an 80% ortholog correlation while the zebrafish has a total of 26,000 genes with 71.4% of human genes. Zebrafish and medaka offer several advantages as models for investigating human disorders. Firstly, the cost-effectiveness of maintaining a lab that is borne out of its small size, short generation time, and short life span is comparably better than higher animal models. Other qualities of zebrafish and medaka are high fecundity and transparent embryos which enhances visualization at different stages of embryogenesis. The purpose of this review is to highlight the anatomic and transcriptomic differences between the two species and the successes recorded so far using these teleost fishes complementarily in research, for instance in genetic manipulation. These differences which are due to evolutionary distance are the reasons why the two systems have been found complimentary.