Mitochondrial diseases are a group of heterogeneous pathologies with decreased cellular energy production as a common denominator. Defects in the oxidative phosphorylation (OXPHOS) system, the most frequent one in humans being isolated complex I deficiency (OMIM 252010), underlie this disturbed-energy generation. As biogenesis of OXPHOS complexes is under dual genetic control, with complex II being the sole exception, mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) are found. Increasing knowledge is becoming available with respect to the pathophysiology and cellular consequences of OXPHOS dysfunction. This aids the rational design of new treatment strategies. Recently, the first successful treatment trials were carried out in patient-derived cell lines. In these studies chemical compounds were used that target cellular aberrations induced by complex I dysfunction. Before the field of human clinical trials is entered, it is necessary to study the effects of these compounds with respect to toxicity, pharmacokinetics and therapeutic potential in suitable animal models. Here, we discuss two recent mouse models for nDNA-encoded complex I deficiency and their tissue-specific knock-outs.