Recent work has shown that: 1) loss of transforming growth factor-β response is associated with malignant progression, 2) maintenance of autocrine negative transforming growth factor-β activity is a key impediment to malignant progression, and 3) the major mechanism for loss of RII expression in replication error-positive colorectal cancer patients is mutation of the poly A tract of the transforming growth factor-β receptor type II (RII) gene resulting in the generation of a premature STOP codon. Major issues for the role of Rll in cancer are identified as the determination of the penetrance of mechanisms of Rll loss in non-replication error tumors and other types of malignancies in addition to colon cancer. Analysis of mechanism of Rll loss may prove to have clinical use in defining the clinical course of subset of different types of malignancies and, in addition, it may result in the identification of new therapeutic targets and approaches for some subsets of cancers.