Renal fibrosis is the hallmark of various chronic kidney diseases (CKD). Transforming growth factor beta (TGF-β) is recognized as a vital mediator in renal fibrosis as it induces production of extracellular matrix to cause renal scarring. The precise roles of individual Smads, receptors, and co-repressors have been recently characterized, and the results reveal the complexity of TGF-β signaling during CKD. Smad2 and Smad7 play protective roles; however, Smad3 plays a pathogenic role in CKD. Smad4 enhances Smad3-mediated renal fibrosis. Heat-shock protein also plays an essential role in TGF-β/Smad-mediated renal fibrosis. Recent findings demonstrate that microRNAs are critical downstream effectors of TGF-β/Smad3 signaling in renal fibrosis. Thus, targeting the downstream TGF-β/Smad3 signaling pathway by gene transfer of either Smad7- or Smad3-dependent microRNAs, and by applying Smad3 inhibitor and Smad7 agonist may offer a specific and effective therapeutic strategy for renal fibrosis in CKD.