Autophagy is a self-degradation process in which the cytoplasmic cargoes are delivered to the lysosomes for degradation. As the cargoes are degraded/recycled, the autophagy process maintains the cellular homeostasis. Anti-cancer therapies induce apoptosis and autophagy concomitantly, and the induced autophagy normally prevents stress responses that are being induced. In such cases, the inhibition of autophagy can be a reasonable strategy to enhance the efficacy of anti-cancer therapies. However, recent studies have shown that autophagy induced by anti-cancer drugs causes cell death/apoptosis induction, indicating a controversial role of autophagy in cancer cell survival or death/apoptosis. Therefore, in the present review, we aimed to assess the signaling mechanisms involved in autophagy and cell death/apoptosis induction during anti-cancer therapies. This review summarizes the process of autophagy, autophagy flux and its blockade, and measurement and interpretation of autophagy flux. Further, it describes the signaling pathways involved in the blockade of autophagy flux and the role of signaling molecules accumulated by autophagy blockade in cell death/apoptosis in various cancer cells during anti-cancer therapies. Altogether, it implies that factors such as types of cancer, drug therapies, and characteristics of autophagy should be evaluated before targeting autophagy for cancer treatment.