Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA), is an infrequent, but potentially fatal, type of immune-mediated vascular disease. The site of the aberrant immune reaction, the mural layers of the artery, is strictly defined by vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts, which engage in an interaction with T cells and macrophages to, ultimately, cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of effector cytokines, all known as critical mediators in host-protective immunity, have been identified in vasculitic lesions. Two dominant cytokine clusters—the IL-6–IL-17 axis and the IL-12–IFN-γ axis—have been linked to disease activity. These two clusters seem to serve different roles in the vasculitic process. The IL-6–IL-17 cluster is highly responsive to standard corticosteroid therapy, whereas the IL-12–IFN-γ cluster is resistant to steroid-mediated immunosuppression. The information exchange between vascular and immune cells and stabilization of the vasculitic process involves members of the Notch receptor and ligand family. Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, might enable a more tailored therapeutic approach that avoids unwanted adverse effects of aggressive immunosuppression.