Programmed cell death and its morphological manifestation termed apoptosis is a conserved pathway that appears to operate in all multicellular organisms. During embryonic development, cell death is essential for successful organogenesis, and apoptosis also operates in adult organisms to maintain normal cellular homeostasis. The removal of disordered cells by a controlled cellular mechanism is especially critical in long-lived mammals that must integrate multiple physiological as well as pathological death signals. Gain- and loss-of-function models of genes in the core apoptotic pathway suggest that perturbation of cellular homeostasis can be a primary pathogenic event that results in disease. Indeed, there is now compelling evidence that insufficient apoptosis can manifest as cancer or autoimmunity, whereas accelerated cell death is evident in acute and chronic degenerative diseases, further highlighting the fact that deregulation of cell death pathways has major health implications. Not surprisingly, during the past 25 years a huge endeavour aimed at unravelling this fundamental biological process has led to major advances in our understanding of cell death pathways. Therapeutic strategies to manipulate apoptosis have immense potential and this review highlights several potentially viable drug targets for modulating cell death that have been discovered from the elegant work of many scientists in elucidating the protein components and key regulators of apoptosis signalling pathways.