Renal fibrosis, i.e. the replacement of functional tissue with scar tissue, represents the pathological correlate for chronic kidney disease (CKD). A great number of renal diseases lead to CKD and thereby to renal fibrosis. Therefore, renal fibrosis represents an excellent treatment option for patients with CKD. Here we discuss the problems with the preclinical identification and testing of potential factors and therapeutic approaches for renal fibrosis as well as obstacles in the translation of these results to clinical practice. We present the preclinical evidence for the role of novel molecules involved in renal fibrosis, e.g. platelet-derived growth factors (PDGF), C5a or peroxisome proliferator-activated receptor-α (PPAR-α).