Abstract The CNS is tightly regulated to maintain immune surveillance and efficiently respond to injury and infections. The current appreciation that specialized “brain-adjacent” regions in the CNS are in fact not immune privileged during the steady state, and that immune cells can take up residence in more immune-privileged areas of the CNS during inflammation with consequences on the adjacent brain parenchyma, beg the question of what cell types support CNS immunity. As they do in secondary lymphoid organs, we provide evidence in this review that stromal cells also underpin brain-resident immune cells. We review the organization and function of stromal cells in different anatomical compartments of the CNS and discuss their capacity to rapidly establish and elaborate an immune-competent niche that further sustains immune cells entering the CNS from the periphery. In summary, we argue that stromal cells are key cellular agents that support CNS-compartmentalized immunity.