Substantive evidence exists that genetic factors play a pivotal role in susceptibility to ankylosing spondylitis (AS). HLA-B27 remains the most convincing and universal association of a genetic factor with AS. Over the last decade there has been immense interest in elucidating genetic variants outside the major histocompatibility complex region. Due to larger AS datasets along with recent advancements in the characterization of genetic markers and large-scale genotyping platforms, replicated non-major histocompatibility candidates have now emerged. This article reviews the current evidence regarding the genetics of AS, with an emphasis on the recent major advances, and it discusses the challenges and limitations in interpreting these studies.