Cytokines are a group of secreted proteins that display diverse biological activity. They are especially important in the body's response to injury. They subserve a variety of both autocrine and paracrine functions by activating numerous intracellular second-messenger signaling pathways. Cytokines are known to mediate many inflammatory processes, and the inappropriate presence of cytokines in the central nervous system (CNS) has been implicated in a number of disease states. This article focuses on the biological role of two cytokines, namely: tumor necrosis factor α (TNF-α), and interferon-gamma (IFN-γ), in the progression of neurologic disorders such as multiple sclerosis (MS) and AIDS dementia complex (ADC), with an emphasis on cytokine effects on glial cells. We discuss the cellular source of each cytokine within the CNS, their receptors, and what signaling pathways are involved in mediating their actions. We also describe recent findings indicating that HIV viral proteins, i.e., gp120, can activate cells of the CNS in a comparable manner as cytokines, and discuss the second messengers that mediate gp120-induced responses. We conclude by identifying potentially important areas of cytokine research in the context of neurologic disease.