The mortality related to AIDS became under control, at the last decade, after HAART was introduced. Nonetheless, soon after the first NRTI was developed, multiple side effects were described. These side effects are often the main shortcoming for HIV infected patients with antiretroviral therapy by now, since other threats like opportunistic infections are rare and HIV infection is a more chronic disease. As a class side effect, mitochondrial toxicity can express from an asymptomatic hiperlactacidemia up to a lifethreatening lactic acidosis. Other NRTI side effects are lipodystrophy (a complex morphometabolic syndrome), peripheral neuropathy, pancreatitis and hypersensitivity reaction with abacavir. This review explores pathophysiology, clinical features and therapeutic options for each one of the major side effects of NRTI, except AZT.