Interstitial fibrosis with tubule atrophy (IF/TA) is the response to virtually any sustained kidney injury and correlates inversely with kidney function and allograft survival. IF/TA is driven by various pathways that include hypoxia, renin-angiotensin-aldosterone system, transforming growth factor (TGF)-β signaling, cellular rejection, inflammation and others. In this review we will focus on key pathways in the progress of renal fibrosis, diagnosis and therapy of allograft fibrosis. This review discusses the role and origin of myofibroblasts as matrix producing cells and therapeutic targets in renal fibrosis with a particular focus on renal allografts. We summarize current trends to use multi-omic approaches to identify new biomarkers for IF/TA detection and to predict allograft survival. Furthermore, we review current imaging strategies that might help to identify and follow-up IF/TA complementary or as alternative to invasive biopsies. We further discuss current clinical trials and therapeutic strategies to treat kidney fibrosis.Supplemental Visual Abstract; http://links.lww.com/TP/C141.