The mitochondrial electron transport chain (mtETC) consists of four multi-subunit enzyme complexes. Complex I or NADH:ubiquinone oxidoreductase, the largest mtETC multisubunit complex, consists of approximately 41 subunits. Seven of these subunits are encoded by the mitochondrial genome, the remainder by the nuclear genome. Among the mitochondriocytopathies, complex I deficiencies are encountered frequently. Although some complex I deficiencies have been associated with mitochondrial DNA mutations, the genetic defect has not been elucidated in the majority of complex I-deficient patients. It is expected that many of these patients have mutations in the nuclear-encoded subunits of this complex, so vital for cellular energy production. After a brief summary of the current knowledge of complex I from cow, bacteria and fungi, this review presents the state of the art of the knowledge of the human nuclear-encoded complex I genes which, in the last 18 months, has made enormous progress. At present, the complete gene structure of four subunits and the cDNA structure of 18 of the 34 complex I nuclear-encoded subunits are known. Mapping of these subunits shows a random distribution over the chromosomes. The chromosomal localization is known for 14 complex I genes. Recently, the first mutation, a 5 bp duplication in the 18 kDa (AQDQ) subunit, has been reported. We expect that within 1 year all human nuclear-encoded complex I subunits will be cloned. Mutational analysis of these subunits is warranted in complex I-deficient patients and will not only be important for genetic counselling but will also extend the knowledge regarding the functional properties of the individual human complex I subunits.