Defective mismatch repair (MMR) in humans causes hereditary nonpolyposis colorectal cancer. This genetic predisposition to colon cancer is linked to heterozygous familial mutations, and loss-of-heterozygosity is necessary for tumor development. Existing mouse knockout models show only partial overlap in the tumor spectrum. Novel zebrafish knockout mutants for the MMR genes msh6, msh2 and mlh1 were generated by target-selected mutagenesis. These fish were found to display microsatellite instability and to develop tumors. Although the tumor spectrum is different from the mouse, it does partially resemble the spectrum of rare patient cases with biallelic MMR mutations. MMR-deficient fish develop predominantly neurofibromas/malignant peripheral nerve sheath tumors, but several other tumor types were also found. The image shows high (first row) and medium (second row) magnifications of histological cross sections (third row) as well as macroscopical images (fourth row) of an ocular neurofibroma (first column), an olfactory neuroblastoma (second column), a primitive neuroectodermal tumor in the brain (third column), and a hemangiosarcoma (fourth column) that were identified in msh6-/- and mlh1-/- fish. Our work shows that the zebrafish is a useful cancer model that provides new insights and experimental possibilities, and complements studies in mouse models and humans. For details, see the article by Feitsma et al. on page 5059 of this issue.