The ATG8 family proteins are critical players in autophagy, a cytoprotective process that mediates degradation of cytosolic cargo. During autophagy, ATG8s conjugate to autophagosome membranes to facilitate cargo recruitment, autophagosome biogenesis, transport, and fusion with lysosomes, for cargo degradation. In addition to these canonical functions, recent reports demonstrate that ATG8s are also delivered to single-membrane organelles, which leads to highly divergent degradative or secretory fates, vesicle maturation, and cargo specification. The association of ATG8s with different vesicles involves complex regulatory mechanisms still to be fully elucidated. Whether individual ATG8 family members play unique canonical or non-canonical roles, also remains unclear. This review summarizes the many open molecular questions regarding ATG8s that are only beginning to be unraveled. Macroautophagy is a conserved cytoprotective process, that facilitates the degradation of damaged or unwanted cellular components and pathogens, collectively termed cargo.ATG8 proteins play key functions during macroautophagy, upon conjugation to double-membrane vesicles, termed autophagosomes, which sequester cargo for lysosomal degradation.In addition to their canonical functions in macroautophagy, ATG8s also function in non-canonical pathways that do not involve autophagosome formation, and in such cases, ATG8s can be targeted to single-membrane vesicles with roles in divergent processes including cargo degradation and secretion.The canonical and non-canonical functions of ATG8 proteins are regulated, at least in part, by the autophagy conjugation machinery, and possibly the unique interactome that ATG8s have at distinct cellular locations.