This chapter discusses NADH-ubiquinone oxidoreductase (NADH dehydrogenase of the respiratory chain). NADH-ubiquinone reductase is recognized as the most complex mitochondria1 enzyme. Reviews during the past decade have focused on selected aspects, such as its structure, its iron-sulfur clusters, and the molecular biology of the enzyme. As the resolution of questions, concerning the enzyme often hinges on information derived from all these disciplines, as well as from the catalytic properties of the enzyme, this chapter reviews attempt to synthesize available information from a variety of sources. The first purified preparation derived from the respiratory chain-linked NADH dehydrogenase was the “DPNH-cytochrome c reductase” of Mahler et al. It was soon recognized to be a fragment of the intact enzyme, devoid of its iron-sulfur clusters, with greatly altered catalytic properties, it retained the ability to oxidize NADH, albeit with oxidants which do not react with the native enzyme. Nevertheless, this was a significant advance as this fragment of three subunits was water-soluble, could be purified by classical procedures, and, much later served to identify the substrate and flavin binding subunits in other sources.