Autophagy, an evolutionary conserved intracellular lysosome-dependent catabolic process, is an important mechanism for cellular homeostasis and survival during pathologic stress conditions in the kidney, such as ischemia-reperfusion injury (IRI). However, stimulation of autophagy has been described to both improve and exacerbate IRI in the kidney. We summarize the current understanding of autophagy in renal IRI and discuss possible reasons for these contradictory findings. Furthermore, we hypothesize that autophagy plays a dual role in renal IRI, having both protective and detrimental properties, depending on the duration of the ischemic period and the phase of the IRI process. Finally, we discuss the influence of currently used diuretics and immunosuppressive drugs on autophagy, underscoring the need to clarify the puzzling role of autophagy in renal IRI.