This chapter focuses on how the immune system is thought to contribute to the multiple sclerosis (MS) process through the different disease phases, including initiation and propagation, and in different anatomical compartments. Several subsets of regulatory T-cells are capable of inhibiting activation of other T-cells, including suppression of autoimmune responses. Clinical trials of B-cell depletion with rituximab and more recently ocrelizumab have demonstrated substantial reductions in new brain lesions, and relapses in MS patients. The innate immune system rapidly senses foreign pathogen-associated structures without the need for adaptive antigen-specific recognition or memory responses. The presence of clonally expanded CD4 and CD8 T-cells persisting in the CNS, suggests that T-cells can be activated or re-activated within the central nervous system (CNS) compartment. Cellular immune responses and soluble factors can have protective and potentially growth permissive influences capable of limiting injury, as well as promoting survival and repair of neural elements.