Mitochondria differ from other subcellular organelles in that they contain their own DNA (mitochondrial DNA [mtDNA]). In mitochondrial disorders, not only does energy failure in tissues and organs result, with a variety of clinical symptoms, but the metabolic block at the end of the anaerobic glycolysis can also lead to excessive pyruvate and lactate accumulation. Lactic acidosis, therefore, can be a manifestation of mitochondrial dysfunction. Symptomatic hyperlactatemia associated with antiretroviral therapy is linked to the mitochondrial respiratory-chain impairment in HIV disease. The recent availability of antiretroviral drugs has substantially reduced HIV-associated mortality and morbidity through decreased viral burden and immune restoration. Mitochondria are the site of generation of most of the cellular ATP pool. The conversion of one molecule of glucose to pyruvate or lactate is associated with the net formation of two molecules of ATP. Nucleoside analog reverse transcriptase inhibitors (NRTI)-related mitochondrial toxicity appears to be the major factor responsible for hyperlactatemia and lactic acidosis in patients with HIV disease. All metabolic acidoses have profound effects on the respiratory, cardiac, and nervous system. It seems essential to discontinue all antiretroviral drugs at the time of NRTI-associated lactic acidosis (NALA) diagnosis; however, surviving patients often need to continue antiretroviral therapy.