Renal fibrosis is a condition characterized by excessive extracellular matrix accumulation in the kidney. Representing the final common result of a variety of injuries, it can lead to chronic kidney disease and end-stage renal disease. Although major efforts have been made in understanding the process of renal fibrosis, attempts to halt its progression have been successful only in a laboratory setting with limited success in clinical practice. Here, we review the current knowledge on the process of renal fibrogenesis and the emerging anti-fibrotic drugs that have shown encouraging results in experimental models and were subsequently tested in clinical trials. We also propose possible explanations that may account for clinical trial failures and poor translation outcomes. Finally, we discuss alternative therapeutic options and future directions in which anti-fibrotic treatments may be coupled with drugs that can enhance endogenous tissue regeneration.