Ankylosing Spondylitis (AS) is a debilitating rheumatic disease that gives young adults a severe form of arthritis with pain and stiffness in the axial skeleton. After the discovery of Human leukocyte antigen B27 (HLA-B27), several hypotheses have been suggested to uncover the exact etiology of AS. The tendency of HLA-B27 to form unusual structures results in recognition and activation of crucial components in innate immune system. Moreover, cellular and soluble arms of the innate response are frequently observed within the affected tissues. Genome-wide analysis has also shown the association of several innate immune-related pathways and cytokines, which act as the effective therapeutic targets in AS. Given the importance of innate immune system, we present a general overview of innate immune components and their involvement in the pathogenesis of AS. In our belief, this kind of explanation can hopefully provide new perspectives for diagnosis and treatment of these patients in the future.