To maintain cellular homeostasis long-lived and toxic cellular components must be degraded. Due to their size, large protein aggregates and long-lived organelles are completely inaccessible to the proteasome, the major protein degradation machinery in the cell. Instead, cells degrade large cytosolic material through autophagy, a process in which double membrane vesicles engulf cytoplasmic material and target it to the vacuole or lysosome for degradation. The sequestering of autophagic cargo can occur by either a non-selective (bulk) or a selective mechanism. Selective autophagy can lead to the capture of mitochondria, peroxisomes, lipid droplets, large protein aggregates and intracellular pathogens. Defective selective autophagy has been correlated with tumorigenesis, chronic infection and neurodegenerative disease. We are using protein crystallography, NMR spectroscopy, small angle X-ray scattering, biochemistry and cell biology to dissect the molecular mechanisms governing this important cellular pathway. We are predominantly using the selective autophagy of mitochondria in yeast as a model system to investigate the mechanisms of selective autophagy initiation. Gaining an understanding of the molecular mechanisms of selective autophagy will allow for the development of novel therapeutics for the treatment of cancer, neurodegeneration, and infectious diseases.