A wide range of pathophysiological changes are involved in the progression of chronic liver disease (CLD). The multifunctional cytokine transforming growth factor beta (TGF beta) can cross talk with other signaling pathways and mediate nearly every aspect of cell physiology from growth to differentiation and cell death. TGFP can maintain immune response homeostasis and mediate wound-healing responses. Additionally, not only can TGFO prevent the occurrence of hepatocarcinoma by regulating the proliferation of hepatic progenitor cells, TGFO can also play important roles in blunting inflammation by interfering with tumor inhibition response generated by inflammatory mediators. The TGF beta/Smad signaling pathway is an important response that is mediated by TGF beta. This pathway also plays multiple functions in the progression of chronic liver disease. The pleiotropic effects of TGF beta and TGF beta/Smad signaling create challenges in the treatment of CLD under conditions that might interfere with the TGF beta signaling pathway. Detailed understanding of the pleiotropic roles of TGF beta signaling in CLD might assist in the selection of more accurate therapeutic approaches, and in the targeting of the right type of cell in the development of treatment strategies, and ultimately in achieving the desired therapeutic effects.