The sequencing of the genome in human and in different mammals unraveled the structure and the general organization of the genes. Nevertheless determining the role and function of genes is still a major issue: with more than two thirds of the genes with almost a complete lack of functional annotation, and little information available for non-coding regions. Consequently understanding a disease, in which a genetic variation is attached in human population, is still a challenge that needs to be taken up. Within this frame, the mouse is the model organism of choice with elaborated, and still growing, genetics and phenotyping tools. Elucidating the function of its genome will, among others, lead to major evolution in biological research, certainly opening new fundamental avenues, and will promote biotechnological and pharmacological innovations with a better understanding of human diseases. The functional annotation of the mouse genome, already started, will be an essential tool to identify and validate new targets for the development of therapeutics and to reduce the impact of diseases.