Non-Hodgkin's lymphoma (NHL) is a disease of increasingly serious proportions. The highest incidence rate in the world is seen in the United States and Canada, with forty to fifty thousand new cases per year in the U.S. NHL is the sixth most common cancer and the sixth most common cause of cancer death, accounting for 4% of all cancers and 4% of cancer-related deaths. There is a clear need for relevant animal models of lymphoma that provide preclinical tools. Our objective is to create a porcine model of lymphoma analogous to the human disease. Genetically engineered porcine tumors may prove to be invaluable for: (1) determining the efficacy of anti-cancer drugs; (2) studying the process of tumorigenesis; and (3) producing cancer in a genetically compliant animal model that is physiologically more similar to humans than rodents. We have previously shown that solid tumors could be readily induced in immunosuppressed pigs via the expression of proteins disrupting the p53 tumor suppressor pathway, and activating c-Myc and Ras pathways, all of which are commonly corrupted in human cancers. In an attempt to induce a less immunogenic tumor with a defined phenotype retroviral vectors encoding four genes (Cyclin d1, CDK 4, c-Myc, and H-Ras) were constructed and injected SC into the mammary area and/or behind an ear, or IV via the ear vein. Both challenge routes induced T-cell lymphoma in the absence of immunosuppression. The effects of vector dose responses are currently being evaluated and future studies will attempt to induce tumors in cloned animals, thus producing tumors that can be transferred to any number of identical animals to study the process of tumorigenesis and cancer.