The adenomatous polyposis coli (APC) tumor suppressor is an essential negative regulator in the evolutionarily conserved Wnt/Wingless (Wg) signal transduction pathway. During normal development, Wnt signaling is required not only to induce cell proliferation and cell fate specification, but also to induce apoptotic cell death. However in some malignant states triggered by APC loss, inappropriate activation of Wnt signaling promotes cell survival and inhibits cell death, indicating that the cellular response to APC loss and Wnt signaling is highly dependent on cell context. This chapter summarizes our current understanding of the role of APC and Wnt signaling in the regulation of apoptosis, based upon studies from fly and mouse in vivo models, as well as cultured carcinoma cells.