Abstract: Mitochondria provide energy required for normal cell function and thus tissue function by producing Adenosine Triphosphate (ATP) via oxidative phosphorylation. They also regulate a number of other cellular processes, including apoptosis. Nucleoside Reverse Transcriptase Inhibitors (nRTIs) remain the cornerstone of Highly Active Antiretroviral Therapy (HAART) combination regimens. However, it has been known for some time that these agents have the potential to cause varied side effects, many of which are thought to be due to their effects on mitochondria. nRTIs can affect the function of this enzyme and this may lead to depletion of mitochondrial DNA or qualitative changes. Various clinical and in vitro studies have shown that nRTIs are associated with mitochondrial dysfunction in different tissues, although the weight of evidence is limited in many cases. The heterogeneity in the tissues affected by the different drugs raises interesting questions and possible explanations include differential distribution or activation of these agents. This study gives an overview of the major recognised toxicities associated with nRTI use in Human Immunodeficiency syndrome (HIV) therapy and evidence for mitochondrial dysfunction in these complications.