Smad4/DPC4 is a tumor suppressor gene frequently inactivated in gastrointestinal carcinomas. Smad4 encodes a key intracellular transmitter for signals of the TGF-beta superfamily of cytokines. TGF-beta potently inhibits the growth of normal epithelial cells but tumor cells are frequently resistant; thus, it has been assumed that loss of Smad4 during tumor progression relieves this inhibition. Mediating TGF-beta responses is only one of the many putative functions of Smad4 as a signaling molecule. Smad proteins are versatile transcriptional co-modulators whose activities depend on the genetic makeup of a cell. We have used restoration of Smad4 in deficient cancer cells as an unbiased approach to decipher Smad4's tumor suppressor functions. Stable reexpression of Smad4 in human colon and pancreatic cancer cells potently suppressed tumor growth in vivo in nude mice. Surprisingly, it was not adequate to suppress tumor cell growth in vitro, nor did it restore TGF-beta responsiveness. Rather, Smad4 restoration influenced angiogenesis, decreasing expression of vascular endothelial growth factor and increasing expression of thrombospondin-1. These findings suggest that the acquisition of TGF-beta resistance and loss of Smad4 may be independent consecutive events in the tumorigenic process. They define the control of an angiogenic switch as a novel alternative mechanism of tumor suppression for Smad4.