EpCAM is a well-established pancarcinoma-associated target antigen that has been used in a variety of therapeutic approaches. Of particular appeal are those strategies that aim to retarget and locally activate immune effector mechanisms involving apoptosis. Cancer cells typically employ various strategies to evade recognition and elimination by immune effector cells, including low or absent expression of MHCI molecules and active elimination of tumor infiltrating immune cells. In addition, cancer cells show an increased resistance towards endogenous pro-apoptotic stimuli due to aberrancies in their apoptotic machinery. However, compelling evidence indicates that cancer cells are often reliant on these molecular aberrations for continued cell survival. This pivotal role of immune evasion and apoptosis resistance has fueled the quest for therapeutic strategies that can selectively retarget and reactivate immune effector cells or molecules, whereby the balance of cellular fate of cancer cells is selectively tipped towards apoptosis. Here we review and discuss the perspectives for EpCAM-targeted apoptosis induction in cancer by EpCAM-selective bispecific antibodies and TRAIL fusion proteins.