Cell death plays an essential role in the development of organs, homeostasis, and cancer. Apoptosis and programmed necrosis are two major types of cell death, characterized by different cell morphology and pathways. Accumulating evidence shows autophagy as a new alternative target to treat tumor resistance. Besides its well-known pro-survival role, autophagy can be a physiological cell death process linking apoptosis and programmed necrosis cell death pathways, by various molecular mediators. Here, we summarize the effects of pharmacologically active compounds as modulators of different types of cancer cell death depending on the cellular context. Indeed, current findings show that both natural and synthetic compounds regulate the interplay between apoptosis, autophagy and necroptosis stimulating common molecular mediators and sharing common organelles. In response to specific stimuli, the same death signal can cause cells to switch from one cell death modality to another depending on the cellular setting. The discovery of important interconnections between the different cell death mediators and signaling pathways, regulated by pharmacologically active compounds, presents novel opportunities for the targeted treatment of cancer. The aim of this review is to highlight the potential role of these compounds for context-specific anticancer therapy.