Rodent models of human diseases serve a vital role in translating bench observations to bedside therapies. In vivo manipulation of these animals allows us to explore the biologic significance of the underlying molecular and biochemical pathways. The study of human cancers has been highly enriched by the observations made from numerous transgenic mouse models. Long before the techniques of genetic engineering were discovered, Dr. Reidar Eker described one of the earliest examples of an autosomal dominant model of renal tumors in a unique strain of rats. They were used in the 1980's by Alfred Knudson to validate the "two-hit" hypothesis and to study the multi-step process of carcinogenesis. Following the identification of the Tsc2 germline mutation in the Eker rat, it became the first rodent model of tuberous sclerosis and has since been exploited in many areas of tumor biology as illustrated in the content of this issue. The focus of our review is to highlight the contribution of the Eker rat towards understanding the Tsc2 signaling pathways in tumorigenesis and evaluating potential therapeutics in the pre-clinical setting.