Abstract: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS). Pathological characteristics of the disease include activation of CNS-intrinsic immune cells, such as microglia and astrocytes, and loss of neuronal connections, myelin and blood-brain barrier (BBB) integrity as well as peripheral immune cell infiltration into the brain. MS has long been considered a predominantly immunological disease, which has led to the development of essentially only immune-directed medications. Within this traditional “outside-in” MS hypothesis, a dysregulation of the peripheral immune system causes immune cell infiltration into the CNS, leading to autoreactivity against myelin sheath components and secondary BBB dysfunction. However, recent findings indicate that overactivation of microglia and astrocytes represents an important first step in MS pathology, as appears to be the case for other neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Within this new hypothesis of CNS-intrinsic neuroinflammation in MS – also known as the “inside-out” model (Titus et al., 2020), the transcription factor nuclear factor-kappa B (NFκB) plays a central role in the brain. In CNS cells, various triggers, such as bacterial and viral infections, oxidative stress and other cellular stressors like protein misfolding and DNA damage, lead to NFκB activation in CNS-immune cells and subsequent production of pro-inflammatory cytokines and adhesion molecules, activation of the inflammasome complex, apoptosis and cell cycle arrest. The production of pro-inflammatory molecules causes a microenvironment which provokes CNS-cell degeneration, and is detrimental for (re)myelination by oligodendrocytes and neuronal regeneration. Neuroinflammatory cascades in the CNS also prevent microglia and astrocytes from exerting their regenerative effects on oligodendrocytes and neurons. In addition, microglia and astrocytes reinforce each other’s negative effects via cytokine-mediated feedback mechanisms, which create a negative loop that further affects the environment for CNS-cell regeneration. Targeting the NFκB pathway may be especially attractive for the treatment of MS as this transcription factor is also involved in regulating inflammatory processes within both the innate and the adaptive peripheral immune systems.