The epithelial cells that line the renal tubule are sometimes severely injured in the course of inflammatory kidney diseases. These renal tubule epithelial cells (RTECs) express some of the Toll-like receptors (TLRs) of the innate immune system. A number of studies have implicated RTECs, together with bone marrow-derived cells, in triggering an innate immune response to bacterial infection and/or ischemic stress. RTECs expressing TLR4, which recognizes lipopolysaccharide (LPS), contribute to defending the host against ascending urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPECs). Activation of TLR2 and TLR4 signaling by endogenous damage-associated molecular patterns controls the inflammatory responses of RTECs and cell apoptosis in kidneys subjected to ischemia/reperfusion (I/R) injury. This review will consider some recent advances in understanding of the role of RTECs in inducing the innate immune response in experimental models of ascending UTIs and renal I/R injury. Arginine vasopressin, which regulates renal water absorption, has been shown to act as a potent modulator of the innate response in collecting duct cells, a preferred intrarenal site for UPEC adhesion. The activation of the mitogen-associated protein kinase ERK1/2 in post-hypoxic RTECs has also been shown to be selectively regulated by TLR2 via the serine-threonine protein phosphatase 5, which is associated with the endoplasmic reticulum resident heat shock protein, gp96, which acts as a master chaperone of TLRs. These findings provide further support for the concept that RTECs are actively involved in triggering the innate immune response, at least in the context of ascending UTIs and I/R injury.