A proteomic analysis of the human autophagy interaction network (AIN) reveals a complex network of 751 interactions among 409 candidate proteins, highlighting the extensive connectivity among sub-networks. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux. Six human ATG8 orthologs (MAP1LC3/GABARAP proteins) interact with 67 proteins, with significant overlap among family members. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for further mechanistic analysis of this critical protein homeostasis pathway. Autophagy is a process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation. It is controlled by pathways that interpret the status of cellular energy, nutrients, and growth factors. Ground-breaking studies in yeast have revealed four conserved signaling modules that control major steps in the process. The Atg1p kinase complex and its mammalian counterpart, the ULK1 complex, control early steps in autophagosome formation. The Vps34p-Vps30p complex and its mammalian PIK3C3-BECN1 counterpart control production of phosphoinositide signals that facilitate assembly of the incipient autophagosome. A ubiquitin-like protein (UBL) conjugation cascade is required for autophagosome maturation and cargo recruitment. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux. The ATG8 autophagy receptor sub-network includes proteins that interact with a conserved surface on ATG8 proteins known to interact with LC3-interacting regions (LIR) in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for further mechanistic analysis of this critical protein homeostasis pathway. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux.A proteomic analysis of the human autophagy interaction network (AIN) reveals a complex network of 751 interactions among 409 candidate proteins, highlighting the extensive connectivity among sub-networks. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux. Six human ATG8 orthologs (MAP1LC3/GABARAP proteins) interact with 67 proteins, with significant overlap among family members. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for further mechanistic analysis of this critical protein homeostasis pathway. Autophagy is a process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation. It is controlled by pathways that interpret the status of cellular energy, nutrients, and growth factors. Ground-breaking studies in yeast have revealed four conserved signaling modules that control major steps in the process. The Atg1p kinase complex and its mammalian counterpart, the ULK1 complex, control early steps in autophagosome formation. The Vps34p-Vps30p complex and its mammalian PIK3C3-BECN1 counterpart control production of phosphoinositide signals that facilitate assembly of the incipient autophagosome. A ubiquitin-like protein (UBL) conjugation cascade is required for autophagosome maturation and cargo recruitment. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux. The ATG8 autophagy receptor sub-network includes proteins that interact with a conserved surface on ATG8 proteins known to interact with LC3-interacting regions (LIR) in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for further mechanistic analysis of this critical protein homeostasis pathway. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux. The AIN includes proteins involved in vesicle trafficking, protein and lipid phosphorylation, and ubiquitination, and their depletion affects autophagosome number or flux.