Abstract: Multiple sclerosis (MS), the most common inflammatory condition of the central nervous system in young adults, is characterized by immune-mediated demyelination and neurodegeneration that translate into heterogeneous clinical phenotypes and disease trajectories. Although focal demyelinating lesions within the white matter are the hallmark of MS pathology, a large amount of lesions has been detected in both cortical and subcortical grey matter tissue. Besides focal pathology, diffuse inflammation and axonal damage are increasingly recognized in normal appearing white matter, as well as grey matter. Among various clinical manifestations, patients with MS may experience epileptic seizures, which can emerge at any time point throughout the disease course. Several clinical factors such as earlier onset of MS, longer disease duration, and higher disability have been related to the increased prevalence of epilepsy in patients with MS (Neuß et al., 2020; Grothe et al., 2021). Acute seizures and epilepsy were also reported in other neuroinflammatory disorders of the central nervous system, e.g., in myelin oligodendrocyte glycoprotein antibody disease, acute disseminated encephalomyelitis or neuromyelitis optica spectrum disorder. A few available neuroimaging and neuropathological studies suggested that the extent of cortical grey matter damage is proportional to the risk of epilepsy occurrence in patients with MS (Calabrese et al., 2012; Nicholas et al., 2016). However, despite the significant progress achieved in elucidating the molecular and cellular basis of MS pathology, mechanisms of increased susceptibility to seizure generation in acute and chronic neuroinflammation are poorly understood, thereby, leaving many questions open. Only a few to list: what are the brain structural fingerprints of epileptic seizures in MS? Is the location of tissue damage within a particular brain region (e.g., hippocampus or thalamus) is critical for initiating epilepsy? Is there a specific “network correlate” of hyperexcitable neuronal circuits and do they render networks vulnerable to ongoing MS-mediated damage? And finally, what are the main “culprit mechanisms” responsible for ictogenesis and epileptogenesis in MS? Based on the aforementioned questions, the overarching aim of this perspective article was to portray the brain network correlates of epilepsy occurrence in MS. First, we describe structural abnormalities of brain tissue associated with a higher susceptibility of epilepsy occurrence. Afterwards, we highlight the network alterations that are linked to epileptogenesis in patients with MS and explain the candidate molecular mechanisms underlying network hyperexcitability. Finally, we provide a conceptual background for future studies.