Neuropathic pain is highly prevalent in patients with cancer and patients with AIDS, has profound effects on ability to function and quality of life, and is undertreated. Multiple obstacles to the adequate treatment of pain in patients with cancer and AIDS have been identified. Specific factors relevant to neuropathic pain, as well as the prevalence of substance abuse disorders in the AIDS population, contribute heavily to the undertreatment of pain in these patients. The differential diagnosis of neuropathic pain in these settings is broad, and a methodical diagnostic approach is required to achieve the primary objective of effective primary therapy. The parallel objective of providing optimal analgesic treatment also requires an aggressive and systematic approach. The presence of comorbid substance abuse issues requires special considerations that ordinarily do not compromise analgesic approaches. This review summarized the neuropathic pain syndromes seen in cancer and in AIDS, presents principles of pain assessment, highlights treatment options, and addresses the issue of pain and chemical dependency.