Autophagy is a cellular process that degrades cytoplasmic contents within lysosomes or vacuoles, recycling macromolecules and generating energy under stress conditions. It plays a critical role in maintaining cellular homeostasis, removing damaged organelles, and protecting cells from toxic proteins. The most common form of autophagy is macroautophagy, which involves the formation of a double-membrane structure called the phagophore, which matures into an autophagosome. The autophagosome then fuses with the lysosome or vacuole, where the cargo is degraded. Recent studies have significantly advanced our understanding of autophagy, particularly in yeast and other eukaryotes, revealing its involvement in various human pathologies, including cancer, neurodegenerative diseases, and diabetes. Despite these advances, many aspects of autophagy remain unclear, including the mechanisms of phagophore formation, the regulation of autophagy induction, and the functions of most autophagy-related proteins. This review focuses on macroautophagy, discussing the discovery of this process in mammalian cells, the donor membrane that forms the phagophore, and the characterization of the autophagy machinery. Key components of the autophagy machinery include the Atg proteins, which are involved in various steps of autophagosome formation, including the initiation of autophagy, membrane delivery, and the expansion of the phagophore. The review also highlights the role of the PtdIns3K complex in autophagy, which generates PtdIns3P, a key molecule that recruits Atg proteins to the phagophore assembly site (PAS). The review further discusses the molecular mechanisms of selective autophagy, including the Cvt pathway, mitophagy, and pexophagy, which involve the recognition of specific cargos by receptors and the subsequent targeting of these cargos to the autophagic machinery. The review also provides an overview of the structural studies of the Atg proteins, including the Atg1 kinase complex, Atg9 complex, and the two Ubl protein conjugation systems. These studies have provided insights into the molecular interactions and functions of the Atg proteins, as well as the structural details of the autophagy machinery. Overall, the review highlights the complexity of autophagy and the need for further research to fully understand its mechanisms and functions.Autophagy is a cellular process that degrades cytoplasmic contents within lysosomes or vacuoles, recycling macromolecules and generating energy under stress conditions. It plays a critical role in maintaining cellular homeostasis, removing damaged organelles, and protecting cells from toxic proteins. The most common form of autophagy is macroautophagy, which involves the formation of a double-membrane structure called the phagophore, which matures into an autophagosome. The autophagosome then fuses with the lysosome or vacuole, where the cargo is degraded. Recent studies have significantly advanced our understanding of autophagy, particularly in yeast and other eukaryotes, revealing its involvement in various human pathologies, including cancer, neurodegenerative diseases, and diabetes. Despite these advances, many aspects of autophagy remain unclear, including the mechanisms of phagophore formation, the regulation of autophagy induction, and the functions of most autophagy-related proteins. This review focuses on macroautophagy, discussing the discovery of this process in mammalian cells, the donor membrane that forms the phagophore, and the characterization of the autophagy machinery. Key components of the autophagy machinery include the Atg proteins, which are involved in various steps of autophagosome formation, including the initiation of autophagy, membrane delivery, and the expansion of the phagophore. The review also highlights the role of the PtdIns3K complex in autophagy, which generates PtdIns3P, a key molecule that recruits Atg proteins to the phagophore assembly site (PAS). The review further discusses the molecular mechanisms of selective autophagy, including the Cvt pathway, mitophagy, and pexophagy, which involve the recognition of specific cargos by receptors and the subsequent targeting of these cargos to the autophagic machinery. The review also provides an overview of the structural studies of the Atg proteins, including the Atg1 kinase complex, Atg9 complex, and the two Ubl protein conjugation systems. These studies have provided insights into the molecular interactions and functions of the Atg proteins, as well as the structural details of the autophagy machinery. Overall, the review highlights the complexity of autophagy and the need for further research to fully understand its mechanisms and functions.