Understanding the biology of inflammation occurring at the entheseal-bone insertion has led to a better knowledge of the main drivers of inflammation in spondyloarthropathies. The clinical efficacy of tumor necrosis factor-α (TNF-α) blockers strongly supports the idea that TNF-α is a key molecule. Yet 40% of patients do not respond appropriately, indicating that other pathways are likely involved in these illnesses. Targeting T cells through a blockade of costimulating (CD28) molecules does not help, and in experimental models of sacroiliitis, targeting interleukin 6 (IL-6) did not provide any useful evidence. Immunohistological and functional data suggest that B cells, Th17, or IL-17A might be important, and indeed preliminary data concerning drugs targeting B cells and IL-17A seem to suggest clinical benefits.