Autophagy is an intracellular self-digestion mechanism, by which cellular components are sorted into double-membrane autophagosomes and delivered to lysosomes for degradation. Cells use autophagy to dispose of wastes and eliminate hazards, while recycling nutrients and tuning metabolism in the process. Through these functions, autophagy promotes cell fitness, genome integrity, tissue homeostasis, and cell survival and growth under stress. Both autophagy upregulation and downregulation have been found in human cancers, suggesting a complex role in tumor development. Accumulating results from autophagy-deficient mice and mouse models of human cancers have demonstrated that autophagy generally suppresses tumor initiation, but promotes tumor progression, in a manner that is dependent on timing and context and modified by specific tumorigenic events. Given the role of autophagy in facilitating tumor growth, autophagy inhibition has gained wide attention as a potential anticancer therapy. Here, we summarize relevant genetic, preclinical, and clinical studies and discuss the multifaceted role of autophagy in cancer, as well as the prospects of autophagy inhibition for cancer therapy. Clin Cancer Res; 21(3); 498–504. ©2014 AACR.