Autophagosome formation is stimulated by canonical VPS34-dependent formation of phosphatidylinositol 3-phosphate [PI(3)P], which recruits effectors such as WIPI2. However, non-canonical VPS34-independent autophagy has also been proposed. We recently described that PI(5)P regulates autophagosome biogenesis, recruits WIPI2, and rescues autophagy in VPS34-inactivated cells. These alternative autophagy-initiating pathways reveal new druggable targets for treating neurodegeneration and cancer.