Renal fibrosis can contribute to progressive damage both to renal structure and function. It is a common pathological process through which chronic kidney disease develops into kidney failure irrespective etiologies, and eventually leads to death. However, there is no available drug to treat renal fibrosis. Lipid aggregation and lipid toxicity within kidney always tightly accompanied chronic kidney disease as well as renal fibrosis. Moreover, accumulated studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can reduce renal fibrosis. Thus, it is an important strategy to correct the dysfunctional lipid metabolism in the kidney by targeting critical regulators of lipid metabolism. This emerging direction brings ideas for the drug target determination to prevent or treat renal fibrosis, which may create bona fide drugs for this thorny disease burden. In this review, we highlight the potential “druggability” of lipid metabolism to resist renal fibrosis and provide current preclinical evidence, exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis roles. Then we introduce the preliminary progress of noncoding RNAs and phytochemicals as promising anti-renal fibrosis drug targets or drugs from the perspective of lipid metabolism. Finally, we discuss the prospects and deficiencies of interfering with lipid reprogramming in the kidney.