The article reviews the role of NF-κB (nuclear factor K-light-chain-enhancer of activated B cells) in inflammation and neuroinflammation, particularly in the central nervous system (CNS). NF-κB is a critical transcription factor that regulates immune and inflammatory responses throughout the body. In the resting state, NF-κB is sequestered by IκB proteins in the cytoplasm. Upon activation, IκB is degraded, allowing NF-κB to translocate to the nucleus and upregulate pro-inflammatory genes. NF-κB activation can be triggered by various stimuli, including proinflammatory cytokines and chemokines, and has cell type-specific effects, often leading to pro-inflammatory cascades. In the CNS, microglia, the primary immune cells, exhibit upregulation of NF-κB upon activation in response to pathological conditions. This activation can lead to cell death and exacerbate disease pathology. The review highlights the multifaceted role of NF-κB in different cell types within the CNS, including neurons, oligodendrocytes, astrocytes, and microglia. Neurons can be both neuroprotective and neurodegenerative, depending on the context. Oligodendrocytes can promote cell survival but also contribute to inflammatory conditions in the CNS. Astrocytes play a role in clearing synaptic glutamate and metabolic control, while microglia are primarily associated with pro-inflammatory responses. The article also discusses the role of NF-κB in specific CNS diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and hypoxic ischemic encephalopathy (HIE). In AD, NF-κB activation is linked to amyloid beta plaques and tau tangles, contributing to neurodegeneration. In ALS, microglial NF-κB activation is associated with motor neuron death. In HIE, NF-κB activation in microglia is a major driver of secondary energy failure and inflammation. Overall, the review emphasizes the importance of understanding the complex relationship between NF-κB and microglial activation in neuroinflammation, highlighting potential therapeutic targets for neuroprotective interventions.The article reviews the role of NF-κB (nuclear factor K-light-chain-enhancer of activated B cells) in inflammation and neuroinflammation, particularly in the central nervous system (CNS). NF-κB is a critical transcription factor that regulates immune and inflammatory responses throughout the body. In the resting state, NF-κB is sequestered by IκB proteins in the cytoplasm. Upon activation, IκB is degraded, allowing NF-κB to translocate to the nucleus and upregulate pro-inflammatory genes. NF-κB activation can be triggered by various stimuli, including proinflammatory cytokines and chemokines, and has cell type-specific effects, often leading to pro-inflammatory cascades. In the CNS, microglia, the primary immune cells, exhibit upregulation of NF-κB upon activation in response to pathological conditions. This activation can lead to cell death and exacerbate disease pathology. The review highlights the multifaceted role of NF-κB in different cell types within the CNS, including neurons, oligodendrocytes, astrocytes, and microglia. Neurons can be both neuroprotective and neurodegenerative, depending on the context. Oligodendrocytes can promote cell survival but also contribute to inflammatory conditions in the CNS. Astrocytes play a role in clearing synaptic glutamate and metabolic control, while microglia are primarily associated with pro-inflammatory responses. The article also discusses the role of NF-κB in specific CNS diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and hypoxic ischemic encephalopathy (HIE). In AD, NF-κB activation is linked to amyloid beta plaques and tau tangles, contributing to neurodegeneration. In ALS, microglial NF-κB activation is associated with motor neuron death. In HIE, NF-κB activation in microglia is a major driver of secondary energy failure and inflammation. Overall, the review emphasizes the importance of understanding the complex relationship between NF-κB and microglial activation in neuroinflammation, highlighting potential therapeutic targets for neuroprotective interventions.