Apoptosis plays a key role in the development of cancer and the response of tumor cells to therapeutic intervention. Recent work using three-dimensional cell culture models underscores the importance of the interactions between epithelial cells–both normal and malignant–and the extracellular matrix that surrounds them in informing life and death decisions. Research in this area is beginning to define the oncogenic pathways that can interfere with this process and the biochemical pathways that transmit signals from proper cell-matrix interactions to promote cell survival.