Endogenous opioid peptides play a variety of roles in the central nervous system (CNS) from development to immune modulation. These functions are mediated mostly via specific opioid receptors uniquely localized in different brain regions and cells. Exogenous opioids can influence and modulate neuronal and glial cell function via an opioid receptor mediated mechanism, leading to either protection or damage of the brain. Mechanisms underlying CNS opioid effects may be mediated via immune mediators, such as cytokines, beta-chemokines, and free radicals (i.e. reactive oxygen intermediates (ROI) and nitric oxide (NO)) produced by activated glial cells (microglia and astrocytes). In the pathogenesis of HIV-1 infection in drug addicts, opiates such as morphine have been postulated to promote the progression of this virus and the development of secondary opportunistic infections. Kappa opioid receptor (KOR) ligands, on the other hand, may play a neuroprotective role. Differences in species, age, sex, cell culture system, stimuli, opioid administration route, concentrations used, strain of infectious agents, and treatment regimes have contributed to many conflicting results in the field of opioid research. More studies are needed to delineate how opioids exert their effects on glial cells as well as neurons with the goal of finding new therapeutic approaches for neurodegenerative diseases, such as AIDS dementia.