Human immunodeficiency virus‐1 (HIV‐1)‐infected and immune‐activated macrophages and microglia secrete neurotoxins. Two of these neurotoxins are the pro‐inflammatory cytokines tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), which are thought to play a major role in inducing neuronal death. Both TNF‐α and IL‐1β increase the permeability of the blood–brain barrier, through which subsequently HIV‐infected monocytes can enter the brain. They both induce over‐stimulation of the NMDA‐receptor via several pathways, resulting in a lethal neuronal increase in Ca²⁺ levels. Additionally, TNF‐α co‐operates with several other proinflammatory mediators to enhance their toxic effects. Although most research has focused on the neurotoxic effects of TNF‐α and IL‐1β in HAD, there is also evidence that these cytokines can be neuroprotective. In this paper the effect of TNF‐α and IL‐1β on neuronal life and death in HAD is discussed.