Publisher Summary This chapter reviews the mode of action of several well-characterized mitochondrial toxins, and discusses their effects in contrast with mechanisms of cell death in various degenerative disorders. The majority of known toxins specifically target components of mitochondrial metabolic pathways. The chapter describes the grouping of toxic agents in terms of their principal target site within the mitochondria, often reflecting effects on components of the mitochondrial respiratory system. In several cases, however, these agents have multiple sites of action because of their affinity for certain chemical moieties present in multiple mitochondrial proteins, demonstrated by cyanide's propensity for Fe3+ containing enzymes which include both complexes II and IV of the electron-transport chain (ETC). The mitochondrial toxin 3-nitropropionic acid (3-NP) irreversibly inhibits the activity of succinate dehydrogenase, a metabolic enzyme that participates in both the tricarboxylic-acid (TCA) cycle and in complexes II–III of the ETC. Systemic administration of this agent to humans, nonhuman primates, and rodents results in central nervous system (CNS) lesions that selectively target subpopulations of striatal neurons, closely replicating the nature and regional specificity of pathological events seen in Huntington's disease (HD).