Transforming growth factor beta (TGFbeta) members are secreted in biologically inactive complexes that must be activated in order to enable binding to their cell surface receptors. Interestingly, many of the proteins that can activate TGFbeta have been implicated in either suppressing or promoting tumorigenesis. Included among these are matrix proteins (thrombospondin-1), receptors (integrins alphanubeta6 and alphanubeta8) and proteases (matrix metalloproteases and plasmin). These proteins cannot only activate TGFbeta, but can also modulate cell responsiveness to TGFbeta. In this section, we review data highlighting the complexity and bidirectionality of TGFbeta matrix interactions within the tumor microenvironment, and propose that these dynamic interactions are a critical spatial and temporal determinant of the effects of TGFbeta on tumorigenesis.