Renal ischemia is a common cause of acute kidney injury in hospitalized patients. In certain settings renal ischemia is unavoidable, such as in kidneys harvested for transplantation. The molecular and cellular mechanisms that lead to the syndrome of ischemic renal injury are complicated and involve multiple cell types within the kidney, including renal epithelium and vasculature. Although it has been difficult to define pharmacologic targets for AKI, emerging information about a newly discovered host defense system is providing hope for novel pharmacologic targets to prevent and treat AKI. Molecular initiators of damage associated with hypoxia involve a phylogenically conserved host defense system called the innate immune system. Data point to an essential role for receptors of the innate immune system, particularly the membrane-bound Toll-like receptors and the intracellular nucleotide-binding oligomerization domain-like receptors. These receptors have been identified in human and rodent kidneys, and many investigators have shown that their deletion protects from experimental ischemia/reperfusion injury (a model for ischemic acute kidney injury). This review details current information about the innate immune system and the ischemic kidney with a focus on the emerging role of intracellular innate immune receptors.