Spondyloarthritis (SpA) refers to a variety of inflammatory rheumatic disorders with strong heritability. Shared genetic predisposition, as shown by familial aggregation, is largely attributable to the major histocompatibility complex (MHC) locus, which was estimated to account for approximately half of the whole disease heritability. The first predisposing allele identified more than 40 years ago is HLA-B27, which is a major gene predisposing to all forms of SpA. However, despite intensive research, its pathogenesis remains uncertain. Other MHC alleles belonging to the class I and class II regions have been identified to exert additional effect. Candidate-gene approaches and genome-wide studies have recently allowed identification of several new loci residing outside of the MHC region that are involved in the predisposition to SpA. Interestingly, some of those new genes, such as ERAP1, ERAP2, and NPEPPS, code for aminopeptidases that are involved in MHC class I presentation and were shown to interact with HLA-B27.