A canonical regulatory pathway involving the members of the Bcl-2 and caspase families has been established to regulate developmental apoptosis in nematodes and flies. However, mutant mice that have major deficiencies in this apoptosis pathway show only relatively minor developmental defects. Recent revelations indicate that multiple mechanisms are involved in regulating cell death during mammalian development, tissue homeostasis, and pathological cell loss. Here, we critically evaluate the evidence demonstrating the existence of alternative cell death mechanisms, including apoptosis of lower organisms in the absence of canonical apoptosis mediators, autophagic cell death, necroptosis, elimination by shedding, keratinocyte death by cornification, and cell-cell cannibalism by entosis. The physiological relevance of alternative cell death mechanisms as primary and backup mechanisms is discussed.