Renal inflammation and fibrosis are key pathological features of acute kidney injury (AKI) and chronic kidney disease (CKD). Smad3 is a critical mediator of TGF-β signaling and plays a pathogenic role in both renal inflammation and fibrosis. Smad3 can be activated not only by TGF-β1 but also by many stress molecules including angiotensin II (Ang II), advanced end products (AGEs), and C-reactive protein (CRP) under disease conditions. In addition, Smad3 can interact with other signaling pathways, such as the ERK/p38 MAPK and NF-κB pathways, to mediate renal inflammation and fibrosis. Mechanistically, Smad3 transcriptionally regulates many downstream target genes including microRNAs and long non-coding RNAs to cause cell death, inflammation, and fibrosis. Thus, targeting Smad3 or its downstream genes specifically related to renal inflammation and fibrosis should provide a novel therapeutic strategy to combat kidney diseases.