Radiation-induced fibrosis (RIF) represents one of the most common long-term adverse effects of curative radiotherapy. Current cancer treatment approaches, involving more intensive radiotherapy regimens, used in combination with systemic agents, will likely be associated with a higher incidence and greater degree of damage to normal tissues, especially RIF. Traditionally, the development of fibrosis after radiation therapy has been considered static and irreversible. Contemporary understanding recognizes RIF as a continuum of responses mediated by molecular pathways that may be amenable to interventions. Preliminary evidence suggests that pharmacological or other interventions may be possible to reverse the manifestation of the injury and restore function to tissues. A variety of strategies have been tested for the management of RIF, although formal trials of these therapies that permit treatment comparisons are unavailable at this time. It is critical that we formally evaluate new management approaches for RIF with larger patient accrual. To this end, it is also important to develop a means of registering its occurrence for outcome analysis and to refer these patients to colleagues familiar with optimal management and enrollment in clinical trials.