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The kidneys are particularly susceptible to ischemia-reperfusion injury (IRI), which occurs when the blood supply is temporarily reduced and then restored. Kidney IRI is the most common form of acute kidney injury (AKI), which often progresses to kidney fibrosis, causing significant patient morbidity and mortality with escalating healthcare costs. There are no effective therapies to prevent AKI or the subsequent progression to kidney fibrosis following IR. This may in part be due to limited understanding of the exact molecular mechanisms that cause kidney injury and fibrosis following IR. Emerging research has identified the involvement of regulated cell death pathways such as necroptosis in kidney IRI. Necroptosis is triggered by recruitment of the intracellular kinases RIPK1 and RIPK3 and activation of the pseudokinase MLKL. Active MLKL causes cell death by plasma membrane rupture, with release of intracellular contents driving “necroinflammation”. RIPK1 and RIPK3 may also have a cell death independent role in the development of kidney fibrosis. In this thesis we performed a detailed analysis of necroptosis in kidney IRI. Using a mouse model of unilateral kidney IRI, we showed that necroptosis contributes to kidney injury following moderate (18 min) but not more severe (20-24 min) ischemia. We identified a shift in cell death mechanism from necroptosis to apoptosis with increasing severity of IRI; apoptosis was also more prominent in necroptosis-defective Mlkl-ko mice subjected to IR. Using a time course study, we explored the kinetics of kidney injury, inflammation and necroptosis following moderate ischemia. Early inflammation and activation of the necroptosis pathway resulted in tubular cell death, driving ongoing necroinflammation. In the absence of necroptosis (i.e. in Mlkl-ko mice), early inflammation and subsequent kidney injury were reduced, indicating that necroptosis and the associated inflammation are important mediators of kidney damage following IR. I