Abstract: The central nervous system (CNS) is an immune-privileged site with tightly-regulated immune responses, a concept proposed by Nobel Laureate Sir Peter Medawar in 1960. Under physiological conditions, only a few T lymphocytes conducting immunosurveillance can infiltrate the CNS. However, in neurodegenerative pathology such as multiple sclerosis (MS), a devastating inflammatory demyelinating disease, transmigration of encephalitogenic T cells from the periphery to the CNS is evident, contributing to the etiology of MS. Among the encephalitogenic T cells, in recent years, interleukin-17-producing T helper 17 (TH17) cells have attracted intensive research interests because of their superior ability to induce MS, as compared to the interferon-γ-producing T helper 1 (TH1) cells that had long been regarded as the primary culprit in the pathogenesis of MS, prior to the discovery of TH17 cells in 2005. An early study showed that C-C chemokine receptor 6 (CCR6)+ TH17 cells are the first encephalitogenic T cells to infiltrate the CNS, which leads to the second wave of infiltration by other neuroinflammatory immune cells including TH1 cells (Reboldi et al., 2009). These T cells drive the development of clinical signs of MS. Conversely, forkhead box P3 (Foxp3)+ regulatory T (Treg) cells suppress TH17 and TH1 cells, mitigating neuroinflammation in MS. Intriguingly, a recent study showed that Treg cells can actually promote remyelination, a key event in neural regeneration (Dombrowski et al., 2017). Analogous to the well-established dichotomy of TH1 and interleukin-4-producing T helper 2 cells, TH17 and Treg cells are considered dichotomous cell fates of activated CD4+ T cells, because of the intimate physical and functional interactions of their master transcriptional factors (retineic-acid-receptor-related orphan nuclear receptor-γ (RORγt) and Foxp3) and the dynamic two-way transdifferentiation between them in various pathogenic conditions. While immune signals (TCR ligation, CD28-mediated co-stimulation, and cytokine) seemingly orchestrate the differentiation of these T cell subsets, an emerging frontier in immunology research is the realization that at a fundamental level, it is the cellular metabolism that dictates the T cell fate decisions including TH17 vs. Treg. To this end, TH17 cells primarily engage glycolysis and fatty acid synthesis (FAS), while Treg cells mainly use oxidative phosphorylation and fatty acid oxidation (FAO) to satisfy their bioenergetic and biosynthetic demands. This suggests that targeting these metabolic pathways may offer a legitimate approach to cure MS by suppressing neurodegenerative TH17 and concomitantly promoting neuroregenerative Treg cells. Thus, in this perspective, we focus on metabolic checkpoints capable of tipping the TH17/Treg balance in favor of Treg formation.