Over the past 5 years, advances in high-throughput techniques and studies involving large cohorts of patients have led to considerable advances in the identification of novel genetic associations and immune pathways involved in ankylosing spondylitis (AS). These discoveries include genes encoding cytokine receptors, transcription factors, signalling molecules and transport proteins. Although progress has been made in understanding the functions and potential pathogenic roles of some of these molecules, much work remains to be done to comprehend their complex interactions and therapeutic potential in AS. In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.