Important breakthroughs in cancer therapy include clinical application of antibodies, such as Rituximab, and small inhibitory molecules, such as Iressa and Velcade. In addition, recent reports have indicated the therapeutic potential of physiological pro-apoptotic proteins such as TRAIL and galectin-1. Although unrelated at first glance, each strategy relies on the deliberate and selective induction of apoptosis in malignant cells. Importantly, therapy-resistance in cancer is frequently associated with de-regulation in the mechanisms that control apoptosis. However, cancer cells are often reliant on these molecular aberrations for survival. Therefore, selective induction of apoptosis in cancer cells but not normal cells seems feasible. Here, we review recent progress and prospects of selected novel anti-cancer approaches that specifically target and sensitize cancer cells to apoptosis.