Tumor necrosis factor alpha (TNF‐α) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF‐α; this de novo production of TNF‐α is an important component of the so‐called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF‐α can potentiate glutamate‐mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca⁺² permeable‐AMPA receptors and NMDA receptors, while decreasing inhibitory GABA_A receptors on neurons. Thus, the net effect of TNF‐α is to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF‐α links the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS). As microglial activation and upregulation of TNF‐α expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF‐α signaling may represent a valuable target for intervention.