The last common ancestor between fish and mammals dates back to the very origin of the vertebrate lineage and today, half of modern vertebrates are fish. It is thus not surprising that several fish species have played important roles in recent years to advance our understanding of vertebrate genome evolution, to inform us on the structure of human genes, and, somewhat more unexpectedly, to provide leads to understanding the function of genes involved in human diseases. Genome sequence comparisons between such distantly related organisms are highly informative due to the accumulation of neutral mutations in nonfunctional regions. Yet humans and fishes share many developmental pathways, organ systems, and physiological mechanisms, making conclusions relevant to human biology. The respective advantages of zebrafish, medaka, Tetraodon, or Takifugu have been well exploited so far with bioinformatics analyses and molecular biology techniques. However the full potential of fish genomics is about to be unleashed with the integration of more traditional disciplines such as biochemistry and physiology, with the study of additional species such as carp, trout, or tilapia and a broadening of its applications to environmental genomics or aquaculture.