Kidney diseases are a major source of morbidity and mortality in humans. In developed countries, mortality owing to chronic kidney disease (CKD) terminating in end-stage renal failure is comparable with that associated with cancer. A full understanding of the mechanisms implicated in the progression of CKD is needed to achieve its prevention and to delay the need for support strategies based on dialysis and transplantation. Renal fibrosis is the unifying feature of progressive renal alterations. In this review, we discuss the current status of possible mechanisms, tools and targets in CKD. Pathophysiological compound identification, biomarker discovery and accurate selection of clinical validation criteria appear to be three key elements needed to develop a successful innovative pharmaceutical approach to treating kidney diseases.