Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resident glial cells within the CNS that culminate into strong neuroinflammation and axonal damage. Most of the current knowledge on the immunopathology of MS has been generated using the rodent model of experimental autoimmune encephalomyelitis (EAE). Among CD4+ T helper cell subsets, interferon gamma (IFN-γ)-producing Th1 cells as well as interleukin 17 (IL-17)-producing Th17 cells are crucial in driving the pathology of EAE. Th1 and Th17 cell differentiation is guided by distinct transcriptional programs induced by polarizing factors. Presumably, following a trigger, some local factors and effector molecules produced by Th1 and Th17 cells facilitate their entry into the CNS and induce a pathological neuroinflammatory response by activating resident glial cells, which further assist massive infiltration of a second wave of immune cells into the CNS. This scenario was evident from the fact that adoptive transfer of in vitro activated myelin oligodendrocyte glycoprotein (MOG)-specific Th1 and Th17 cells into naïve rodent hosts was sufficient to induce EAE (Codarri et al., 2011). Nevertheless, disease severity and clinical manifestation of EAE induced after adoptive transfer of Th1 and Th17 cells were highly variable. Transfer of Th1 cells induced classical paralytic EAE, whereas Th17 cell transfer drove atypical ataxic EAE, an indication that mechanisms used by effector Th1 and Th17 cells in driving neuroinflammation might be different. A number of parameters could account for these differences. First, Th1 and Th17 cells might have different capacities to directly target neurons (Siffrin et al., 2010). Second, by virtue of distinct sets of effector molecules they target and recruit different cells within and towards the CNS and altogether induce a different neuroinflammatory profile. Third, they might have different capacities to regulate repair mechanisms following initial neuroinflammatory damage. Here we focus on the current knowledge of T cell-glial interactions and discuss how effector molecules of Th1 and Th17 cells influence the phenotype and function of resident glial cells within the CNS. There is a great body of evidence describing IFN-γ and IL-17 as major effector molecules of Th1 and Th17 cells, respectively. However, induction of EAE by IFN-γ-/- and IL-17-/- T cells has demonstrated that these factors are dispensable for neuropathology (Codarri et al., 2011). Further studies have identified granulocyte macrophage colony stimulating factor (GM-CSF), largely associated with Th17 cells but also produced by Th1 cells,as an indispensable effector molecule whose overexpression in CD4+ T cells alone was sufficient for driving neuropathology similar to EAE (Codarri et al., 2011; Spath et al., 2017). Following infiltration into the CNS, autoreactive Th1 and Th17 cells are involved in constant crosstalk with microglia and astrocytes and their effector molecules profoundly influence the phenotype and function of these major glial cell types. Microglia are the sentinels of the CNS that rapidly respond to invading pathogens, CNS injury and inflammation. Depending on external cues they can attain pro- (M1-like) or anti-inflammatory (M2-like)phenotypes. Although this dichotomy vastly oversimplifies the plasticity of microglia, the original thought is that an M1-like phenotype is attained by sensing invading pathogens or inflammatory mediators and is considered to be neurotoxic, whereas M2-like microglia are involved in repair mechanisms and are considered to play a neuroprotective role by providing anti-inflammatory mediators and growth factors (Aguzzi et al., 2013). Microglial responses need to be tightly balanced between these phenotypes to maintain the integrity of neural tissue. A sustained pro-inflammatory milieu during MS favors M1-like microglia to populate the lesions triggering demyelination and axonal damage. Similarly, reactive astrogliosis is also a characteristic feature of neurodegenerative disorders like MS. Astrocytes are the most abundant cell type in the CNS with a multitude of functions including support of neural homeostasis. Anatomically astrocytes are active components of the blood-brain barrier (BBB) and are also found in close association with neurons. Therefore they were believed to be less reactive than microglia to avoid any imminent damage to the neural tissue. However, astrocytes do respond to injury by releasing diverse molecules. Primarily, they are a major source of neurotrophic growth factors (nerve growth factor, glial cell-derived neurotrophic factor,ciliary neurotrophic factor, etc.) which drive neurogenesis and assist tissue repair mechanisms. Additionally,astrocytes produce anti-inflammatory factors that dampen any minor inflammation in the CNS and avoid potential damage. Under pathological conditions they also respond to pathogens and infiltrating leukocytes and release a large array of pro-inflammatory cytokines and chemokines,thereby directly contributing to exacerbation of neuroinflammation.