Radiation therapy is a key component of the management of various pelvic tumors, including prostate, gynecological, and anorectal carcinomas. Unfortunately, normal tissues located in the vicinity of target organs are radiosensitive, and long-term cancer survivors may develop late treatment-related injury, most notably radiation-induced fibrosis (RIF) of the small bowel. The cellular mediators of intestinal fibrosis are mesenchymal cells (i.e. myofibroblasts, fibroblasts and smooth muscle cells) which, when activated, serve as the primary collagen-producing cells, and are responsible for excess deposition of extracellular matrix components, eventually leading to intestinal loss of function. For decades, the underlying mechanisms involved in chronic activation of myofibroblasts within the normal tissues were unknown, and the fibrotic process, which ensued, was considered irreversible. Recent advances in the pathogenesis of RIF have demonstrated prolonged upregulation of fibrogenic cytokines, such as Transforming growth factor-β1 (TGF-β1) and its main downstream effector, Connective tissue growth factor (CTGF), in the myofibroblasts of irradiated small bowel. TGF-β1-mediated activation of CTGF gene expression is controlled by Smads, but recently Rho/ROCK signaling has emerged as an alternative pathway involved in the control of CTGF expression in intestinal fibrosis. This article underlines the clinical relevance of RIF as it relates to damage to the small bowel, provides insight to its molecular biology, and finally unveils the potential role of Rho-ROCK inhibitors as emerging strategies to promote RIF reversal.