The mouse is a key model organism for the study of mammalian genetics, development, physiology and biochemistry. The determination of the mouse genome sequence was therefore an early priority in the genome project. A draft sequence became available in 2002 and many chromosomes are now close to being finished. Comparative analysis of the mouse genome sequence with that of the human and other genomes has revealed a wealth of information on genome evolution in the mammalian lineage and assisted in the annotation of both genomes. With the availability of a well-annotated mouse genome sequence, mouse geneticists are now poised to undertake the challenge of generating mutations at every gene in the mouse genome. Systematic mutagenesis of the mouse genome will be an important step towards the first comprehensive functional annotation of a mammalian genome and the identification and characterisation of models for the study of human genetic disease.