Autophagy is an evolutionarily conserved pathway that involves the lysosomal degradation of long-lived cellular proteins and organelles. Our laboratory identified the first mammalian autophagy protein, Beclin 1, in a screen for novel proteins that interact with the apoptosis inhibitor, Bcl-2. Work by our laboratory and others has established that autophagy participates in a number of fundamental biological processes and diseases. Using genetic approaches in different model organisms, we have shown that beclin 1 and autophagy function in tumor suppression, in development and lifespan extension, and in innate antiviral immunity. We have also found that the Bcl-2/Beclin 1 complex provides rheostatic control on autophagy and cell death. Our ongoing research aims to further identify the precise role of autophagy in antimicrobial host defense, in cancer biology, in cell death regulation, and in the prevention of aging and neurodegenerative diseases. To accomplish this goal, we are using a combination of biochemistry, structural biology, molecular biology, and genetic approaches in yeast, C. elegans, and mammalian systems.