Shiga toxins and ricin are ribosome-inactivating proteins which share the property of inhibiting protein synthesis by catalytic inactivation of eukaryotic ribosomes. There is now abundant evidence that Shiga toxins and ricin induce apoptosis in epithelial, endothelial, lymphoid and myeloid cells in vitro, and in multiple organs in animals when administered these toxins. Many studies suggest that protein synthesis inhibition and apoptosis induction mediated by Shiga toxins and ricin may be dissociated. In some cells, non-enzymatic toxin components (Shiga toxin B-subunits, ricin B-chain) appear capable of inducing apoptosis. The toxins appear capable of activating components of both the extrinsic or death receptor-mediated and intrinsic or mitochondrial-mediated pathways of apoptosis induction. Although the toxins have been shown to be capable of activating several cell stress response pathways, the precise signaling mechanisms by which Shiga toxins and ricin induce apoptosis remain to be fully characterized. This chapter provides an overview of studies describing Shiga toxin- and ricin-induced apoptosis and reviews evidence that signaling through the ribotoxic stress response and the unfolded protein response may be involved in apoptosis induction in some cell types.