Histamine has an important but almost underestimated role in the kidney. This organ possesses all the components for histaminergic transmission, as synthetic and metabolic enzymes and histamine receptors are expressed by the resident cells. The differential distribution of histamine receptors reflects the complexity of the anatomical specificity of the kidney; the complexity of this organ could reflect the pleiotropic action of histamine and the redundancy and/or the opposite effects shown by the different receptor isoforms in the specific nephron tract. Here, we provide an overview of the role of histamine in kidney pathophysiology, with a particular focus on the histamine signaling in the resident renal cells.