Viral central nervous system (CNS) infections have an important impact on otherwise healthy individuals. Among others, enteroviruses (EV) are the dominant pathogen in the western world. Additionally, neuroinvasive arboviruses as West Nile virus (WNV) and tick-borne encephalitis virus (TBEV) are gaining in importance probably due to global warming. Seasonal respiratory viruses such as Influenza and severe acute respiratory syndrome coronavirus type 2 (SARS CoV 2) can be associated with a range of neurological complications. Zoonotic viruses as Nipah virus are currently described in small outbreaks but could gain in importance in the future. Still, neuropathogenesis of viral CNS infections is poorly understood with the majority of studies focusing on the blood–brain barrier (BBB) as main entry site to the CNS. Especially, when taking a closer look at in vivo data of patients with viral CNS infections, cerebrospinal fluid (CSF) pleocytosis and CSF cytokines suggest an important role of the blood–CSF barrier (BCSFB). Neurotropic viruses can cross the BCSFB via various mechanisms as direct infection of the choroid plexus epithelial cells, passage trans- or paracellularly, or highjacking transmigrating immune cells. In this chapter, current data on viral CNS infection with a special focus on the BCSFB will be discussed.