Kidney fibrosis is one of the most promising treatment targets in nephrology. To design effective treatment approaches, a detailed understanding of the initiating mechanisms is of great importance. Kim and Pandanilam now find that renal nerves are a major trigger for renal fibrosis. Both afferent and efferent nerve fibers are involved via norepinephrine and α2-adrenergic receptors as well as calcitonin gene-related peptide (CGRP) and its receptors.