Autophagy is a conserved and tightly regulated cellular catabolic process that involves the lysosomal degradation pathway. Intracellular recycling of macromolecules and organelles provided by autophagy is an integral part of normal cellular function and permits cells survival under starvation conditions, maintaining cell growth and the homeostasis of organisms. In addition to its normal role in cell physiology, auto- phagy is closely linked to both tumorigenesis and cancer cell response to treatments. In fact, anticancer drugs can induce autophagy but it remains contro- versial whether this process leads to cancer cell death or protects cancer cells from cellular stress. The role of autophagy in cancer is complex and is likely dependent on tumor type, stage, and genetic context. However, recent evidences demonstrate a tight interconnection of autophagy with several cell death pathways and reveal an active contribution of auto- phagy to cell death. When autophagy is directly in- volved in the death process, the cell death process is designated “autophagic cell death” (ACD). In this review, we will give a comprehensive overview of the autophagic signaling pathway, its role and regulation in cancer cells; moreover, we will try to define the molecular mechanisms at the basis of the autophagic cell death showing that PPAR-γ activation plays a role in the induction of autophagy in cancer cells.