The theoretical basis of chronic allograft rejection remains poorly defined, but is clearly associated with the development of a relatively unique vasculopathy, transplant vascular sclerosis (TVS). The hypothesis that TVS is the cause of chronic rejection has yet to be proven, although it is widely accepted. Accumulating data suggest that, at best, the hypothesis is incomplete. The challenge for transplant investigators is to review the currently available data and to develop a testable, revised version of the hypothesis that explains both the antigen-dependent and antigen-independent contributions to graft vascular remodeling, and that encompasses all reasonable alternative mechanisms of graft failure.