Most currently used anticancer agents are active against proliferating cells. Apoptosis signaling mechanisms induced by many such agents are impaired in tumor cells, leading to therapy resistance. Lysosomes and the endoplasmic reticulum (ER) hold promise as drug targets and mediators of apoptosis signaling which may be less affected by intrinsic or chemotherapy-induced resistance mechanisms. Tumor cell lysosomes contain increased levels of cathepsins, and the release of these enzymes into the cytosol may result in apoptosis or necrosis, as has been reported for TNF-alpha. It is also reported that tumor transformation leads to increased sensitivity to cathepsin B-dependent apoptosis. Tumor cells often show evidence of constitutive ER stress, possibly due to hypoxia and glucose depletion. Various anticancer drugs, including cisplatin and proteasome inhibitors, have been shown to induce ER stress. Manipulating the ER stress response of tumor cells is an interesting therapeutic strategy. We conclude that organelle damage responses can be used to trigger tumor cell death, and that the response to such damage may be triggered in cells that are resistant to conventional DNA-damaging agents.