The molecular mechanisms underlying many human cancers are now reasonably well understood. The challenge now is to bridge the gap between laboratory and clinical oncology, so these accomplishments can be translated into practical benefits for human patients. While genetically modified mice have played a prominent role in basic research, they are less suitable for many preclinical studies. Other animals can provide important complementary resources to aid the development, validation and application of new medicines and procedures. Powerful methods of genetic engineering have now been extended to physiologically more relevant species, particularly the pig, opening the prospect of more representative, genetically defined, cancer models at human scale. We briefly review the field and outline our program to generate gene-targeted pigs carrying mutations in tumour suppressor genes and proto-oncogenes that replicate key lesions responsible for a variety of human cancers. We also highlight some important issues for the future development and usefulness of porcine cancer models.