Autophagy is a highly regulated intracellular trafficking process in which cellular components are engulfed by double-membrane structures and delivered to lysosomes for degradation. Autophagy mediates turnover of aged and damaged cellular components --including whole organelles such as mitochondria and peroxisomes-- and also serves to maintain energy homeostasis during external nutrient deprivation. Impaired or inadquate autophagy is implicated in many disease states and may play a particularly prominent role in neurodegenerative and metabolic diseases. In addition, reduced capacity for autophagy may contribute to many aspects of the progressive cellular dysfunction associated with normal aging. In this seminar, we will discuss new technology for making high-throughput parallel measurements of non-specific 'bulk autophagy' and highly selective mitochondrial autophagy (also known as 'mitophagy'), as well as genetic approaches to modeling cell-specific impairment of autophagy in mice. We will outline current work underway to develop screening strategies for discovering new regulators of autophagy using genome-wide genetic engineering via CRISPR/Cas9-mediated Synergistic Activation Mediator (SAM) libraries.