Peripheral neuropathy, or distal sensory polyneuropathy (DSPN), is the most common neurological problem in HIV disease. DSPN also represents a complex symptom that occurs because of peripheral nerve damage related to advanced HIV disease and in association with the use of antiretroviral therapy-particularly in individuals treated with dideoxynucleosides. Although DSPN is a frequent symptom, the specific pathophysiology is not well understood. The HIV-related neuropathies are commonly categorized as distal sensory polyneuropathies, although antiretroviral toxic neuropathies are described in the literature. Recently, mitochondrial toxicity has been identified as a possible etiology of DSPN. As individuals with HIV/AIDS survive longer, often living for decades with the disease, chronic symptoms like DSPN must be addressed. Pharmacologic approaches, complementary therapies, and self-care behaviors that may improve quality of life and limit symptoms of DSPN are important interventions for clinicians and those living with HIV/AIDS to consider in the management of peripheral neuropathy.