Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease wherein motor neu-ron degeneration leads to muscle weakness, progressive paralysis, and death within 3–5 years ofdiagnosis. Currently, the cause of ALS is unknown but, as with several neurodegenerative diseases,the potential role of neuroinflammation has become an increasingly popular hypothesis in ALS re-search. Indeed, upregulation of neuroinflammatory factors have been observed in both ALS patientsand animal models. One such factor is the inflammatory inducer NF-κB. Besides its connection toinflammation, NF-κB activity can be linked to several genes associated to familial forms of ALS,and many of the environmental risk factors of the disease stimulate NF-κB activation. Collectively,this has led many to hypothesize that NF-κB proteins may play a role in ALS pathogenesis. In thisreview, we discuss the genetic and environmental connections between NF-κB and ALS, as wellas how this pathway may affect different CNS cell types, and finally how this may lead to motorneuron degeneration.