Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas (HPRC) and their transforming potential has been examined both in vitro and in tumor xenografts. To study the influence of these mutations in the mouse germline, we generated mice with targeted mutations in the murine met locus. Five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. Unexpectedly, the different mutant Met lines developed unique tumor profiles including carcinomas, sarcomas, and lymphomas. More surprising was that we observed non-random duplication of the mutant met allele in a majority of tumors from the mutant mouse lines. This selective chromosomal amplification has been observed in patients with HPRC. This study illustrates the importance of activating Met mutations in tumorigenesis and indicates that mutations within the kinase domain distinctly affect downstream signaling. Our Met mutant mice will provide a valuable model for testing Met inhibitors on tumors containing activating mutations present in human cancers and for understanding the molecular events critical for Met-mediated tumorigenesis.