The biophysical properties and the spatial distribution of ion channels define the signaling characteristics of individual neurons. Function, number localization, and ratio of receptor and ion channels are dynamically modulated in response to diverse stimuli and undergo dynamic changes in both physiological and pathological conditions. Increasing evidence indicates that cytokines may specifically interact with receptor and ion channels regulating neuronal excitability, synaptic plasticity, and injury. Interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, two proinflammatory cytokines implicated in various pathophysiological conditions of the CNS, have been particularly studied. Literature data indicate that these cytokines (1) directly and promptly modulate ion channel activity, (2) exert different (and often opposite) effects on the same channels, and (3) act on ion channels both at physiological and pathological concentrations. Consequently, cytokines are now regarded as novel neuromodulators, opening important perspectives in the current view of brain behavior.