Chronic kidney disease (CKD) affects more than 20 million people in the United States and the global burden of this disorder is increasing. Many affected individuals will progress to end stage kidney disease necessitating dialysis or transplantation. CKD is also a major independent contributor to the risk of cardiovascular morbidity and mortality. Tubulointerstitial fibrosis is a final common pathway for most causes of progressive CKD. Currently, there are no clinically available therapies targeting fibrosis that can slow the decline in kidney function. Although it has long been known that TGF-β signaling is a critical mediator of kidney fibrosis, translating this knowledge to the clinic has been challenging. In this review, we highlight some recent insights into the mechanisms of TGF-β signaling that target activation of this cytokine at the site of injury or selectively inhibit pro-fibrotic gene expression. Molecules directed at these targets hold the promise of attaining therapeutic efficacy while limiting toxicity seen with global inhibition of TGF-β. Kidney injury has profound epigenetic effects leading to altered expression of more than a thousand genes. We discuss how drugs targeting epigenetic modifications, some of which are in use for cancer therapy, have the potential to reprogram gene regulatory networks to favor adaptive repair and prevent fibrosis. The lack of reliable biomarkers of kidney fibrosis is a major limitation in designing clinical trials for testing CKD treatments. We conclude by reviewing recent advances in fibrosis biomarker development.