Sequencing of cancer genomes has identified large numbers of recurrent mutations from various tumour types, however the background of non oncogenic “passenger” mutations and allelic variation in these studies can obscure the role that more causal events are playing. Another approach to identifying genes that are mutated in cancer is the use of insertional mutagenesis screens in mice. When newborn mice are infected with slow transforming retroviruses, random insertion of proviruses into the genome of infected host cells leads to deregulation of nearby genes. A proportion of these insertion mutations provide a clonal growth and/or survival advantage to infected cells through activation of oncogenes or inactivation of tumour suppressors, and these cells give rise to lymphoid tumours at three to four months of age. The Sleeping Beauty and piggyBac transposons have been adapted for similar use as oncogenic insertional mutagens to perform screens in selected tissues that are not amenable to infection by slow transforming retroviruses. By cloning the insertion sites from these lymphomas it is possible to identify genes that contribute to malignancy. Loci that are recurrently identified in these screens (referred to as Common Integration Sites or Common Insertion Sites (CISs)) show a significant overlap with the set of known human oncogenes and tumour suppressors, validating the use of this screening approach. These screens create well-controlled panels of tumours in which the causal oncogenic mutations are easily defined by cloning and sequencing of the insertion sites. The screens are a useful complement to human tumour analyses, in part because they provide validation for the oncogenicity of human cancer genes in an independent system using a different mutagen, but also because they yield a thorough coverage of the set of mutations present in each tumour at a cost which is lower by orders of magnitude than the study of human tumours. Our recent screens have identified hundreds of genes mutated in mouse lymphoma and identified hundreds of significant genetic interactions between the somatic insertion mutations and between somatic mutations and the predisposing oncogenic germline alleles present in the mice. Our future screens will focus upon mouse models of follicular lymphoma and diffuse large B cell lymphoma. Mutations in these screens will be validated and investigated further using a panel of human B lymphoma cell lines and by the creation of new mouse models to test the requirement of these genes for tumour maintenance and their potential as therapeutic targets.