Structural and functional alterations of mitochondria are now recognized as the etiology of a growing and wide variety of pathologic disorders. Genetic defects and secondary abnormalities in the synthesis of mitochondrial proteins and enzymes are the underlying cause of diseases affecting the nervous system [1], skeletal and cardiac muscle [1], the liver [2], bone marrow [3], the endocrine and exocrine pancreas [3, 4], kidney, inner ear, and small and large intestines [5] (Table 33.1). Resultant perturbations in mitochondrial function yield defective oxidative phosphorylation (OXPHOS), increased generation of reactive oxygen species (ROS), accumulation of hepatocytic lipids, impairment of other mitochondrial-based metabolic processes, and activation of both apoptotic and necrotic cell death pathways. The spectrum of inherited mitochondrial hepatic and gastrointestinal disorders continues to expand. In addition, mitochondrial dysfunction may be one of the key targets and determinants for hepatocyte survival in other disorders not directly related to the mitochondrion. Thus, the concept of primary (or genetic) and secondary (or acquired) mitochondrial hepatopathies has developed. Because mitochondria possess a distinct and unique extranuclear genome, a new class of maternally inherited mitochondrial diseases has emerged as well. The tissue-specific accumulation over time of new somatic (noninherited) mutations of mitochondrial genes may also be involved in several neurodegenerative diseases [6], hepatopathies, and the process of aging itself [7]. In this chapter, recent advances are reviewed in our understanding of the genetics, the structure and the function of the mitochondrion, a classification for hepatic disorders involving mitochondrial dysfunction is proposed, and the current diagnostic armamentarium and treatment modalities for these disorders are discussed.