Nucleoside analogue reverse transcriptase inhibitors (NRTIs) represent key components of the antiretroviral combinations used to manage HIV infection. A range of nucleoside analogues are currently available which differ in their convenience of administration, frequency of dosing, resistance profile and frequency and severity of adverse effects. Many of the important and treatment limiting side-effects of nucleoside analogues have been suggested to be related to the impact of these agents on mitochondrial DNA polymerase gamma. Depletion of mitochondrial DNA or impacts of these agents on mitochondrial enzymes during chronic nucleoside analogue therapy may lead to cellular respiratory dysfunction and both generalised and tissue specific toxicities. In particular, fatal lactic acidosis represents a rare but clinically important manifestation of nucleoside analogue induced mitochondrial dysfunction. Other potentially severe toxicities which are well-characterised include peripheral neuropathy (PN) and myopathy. Management of potentially mitochondrial toxicity during nucleoside analogue therapy remains a challenge. A range of nutritional supplements, both as treatments and prophylaxes have been proposed and some investigated in vitro but not as yet in vivo. At present, therefore, interruption of nucleoside analogue therapy, or substitution of the probable causative agent with nucleoside analogues which appear better tolerated represent the mainstay of management.