Primary human epithelial renal cells of normal (HRE), paratumoral (pTEC) and tumoral (RCC) origin display important differences, concerning the expression and biological effects of the IL-15/IL-15R system that deeply influences the evolution of the tumour microenvironment. A major distinguishing feature is represented in RCC and pTEC by the loss of the γc chain leading to the assembly of a IL-15Rαβ heterodimer that in response to physiologic concentrations of IL-15 initiates the process of their epithelial–mesenchymal transition (EMT). In contrast, this treatment in HRE cells, which display the IL-15Rαβγc heterotrimer, causes opposite effects inhibiting their drift towards EMT. Thus, IL-15 at physiologic concentrations displays novel functions acting as a major regulator of renal epithelial homeostasis. As second distinguishing feature, RCC and pTEC but not HRE cells express a trans-membrane-bound IL-15 (tmb-IL-15) able to deliver a reverse signal in response to the soluble IL-15Rα chain inducing their EMT. In conclusion, comparison of primary normal (HRE) to primary pathological cells (pTEC and RCC) highlights two major issues: (1) IL-15 is a major regulator of epithelial homeostasis; (2) “apparently normal” pTEC cells, could contribute to organize a generalized “pre-neoplastic” environment committed to favour tumour progression.