Autophagy, lysosome-effected degradation pathway that eliminates damaged and redundant cellular self-constituents, plays a pivotal role in maintaining cell homeostasis. Autophagy is a stress-response triggered under nutrient- and energy-restricted situations, as well as in response to damaging and harmful injuries. Autophagy play an important role in preventing tumorigenic transformation by cooperating with the systems for the quality control of the proteome and of the genome. Defective autophagy may facilitate carcinogenesis, and in cancer cells autophagy may serve a survival function allowing to cope with damages induced by anti-cancer treatments or with the lack of oxygen and nutrients. The composition of the tumour environment impacts on autophagy in cancer cells. In fact, the metabolic cross-talk with stromal cells and their soluble factors, including inflammatory cytokines, can modulate the availability of nutrients, energy and growth factors that eventually modulate autophagy. Autophagy in cancer cells is also modulated epigenetically by changes of the chromatin structures and the presence of microRNA. The fact that autophagy constitutes the integrated response to all metabolic stresses and that can be epigenetically modulated offers the possibility to treat cancer through the use of autophagy-targeted epigenetic modifiers.