Acute kidney injury (AKI) occurs in 5-7% of hospitalized patients in the US. Treatment has largely remained limited to renal replacement measures and supportive care, and mortality remains disturbingly high. Over the last three decades, several pathways have been suggested to account for the derangements in renal function associated with AKI as well as the failure of some individuals to recover. The unfolded protein response (UPR) is a complex intracellular stress response triggered by misfolded proteins within the endoplasmic reticulum. The UPR is a key cellular mechanism that can mediate either cell death or recovery. Due to the large amount of directional transcellular transport, renal tubule cells of the proximal tubule and thick ascending limb of Henle have a high metabolic demand for regulated protein synthesis and trafficking. This makes the renal tubule cells particularly susceptible to ischemic or toxic damage. Factors that induce AKI may initiate the UPR within these cells and lead to a cascade of pro-apoptotic processes. The UPR also contributes to changes in cell polarity and in the location of tubular transport proteins that give rise to abnormal urinary excretory function. Far less is known about the role of the UPR in recovery from AKI but studies indicate that the UPR is involved in preconditioning responses and regeneration of tubular epithelium after injury.