Tumor necrosis factor alpha (TNF) was discovered more than a century ago as endotoxin-induced glycoprotein, which causes haemorrhagic necrosis of sarcomas. Originally described as a circulating factor that causes necrosis of tumours,it now appears that TNF has diverse and critical roles to play in the pathogenic progression of a number of chronic inflammatory disorders, including rheumatoid arthritis, Crohn’s disease, psoriasis, Alzheimer’s disease, ischemic stroke, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. A pivotal role has emerged for TNF as an important contributor to Alzheimer’s disease pathology, as TNF appears to modulate several neuropathological mechanisms in Alzheimer’s disease. Evidence for the involvement of TNF in Alzheimer’s disease pathology and neuronal loss comes from studies of TNF over-expression, TNF localization studies, multiple relationships between TNF and amyloid β-peptide (Aβ), interactions between TNF and the microtubule-associated tau protein, TNF-mediated apoptotic cell death, and association of TNF with several neurotransmitters linked to Alzheimer’s pathology. This review presents TNF as a neuromodulator in pathological progression of Alzheimer’s disease by linking it with several endogenous mediators and advocates its status as a current therapeutic target in the quest to find a cure for Alzheimer’s disease.