Updated project metadata. An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a novel paradigm in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-1) specifically permeated through the plasma membranes of human epithelial breast cancer cells, abolished their mitochondrial-ER network, and triggered cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreased tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cells membranes revealed that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-1 represents therefore a promising anti-cancer lead compound that acts via a unique mechanism.