Human leukocyte antigen (HLA) polymorphisms are the most important genetic risk factors for rheumatoid arthritis (RA), a chronic systemic inflammatory disease of unknown etiology. Certain HLA-DRB1 alleles, known as shared epitope (SE) alleles because they have the same amino-acid sequence at positions 70-74, are associated with susceptibility to RA. A gene dosage effect is present for RA-predisposing SE alleles, and protective alleles show epistasis. An important role of amino-acid polymorphisms at positions 11 and 13 of the HLA-DRβ chain was also reported recently. Rheumatoid factor and anticitrullinated peptide antibodies are present in many RA patients. Similar to extra-articular manifestations, the presence of these autoantibodies is also associated with certain DRB1 alleles. Different frequencies of RA risk alleles in different ethnicities explain the varying prevalence of RA in different populations and suggest genetic heterogeneity of RA with regard to phenotype and population subsets. Some drug-induced hypersensitivity reactions due to disease-modifying antirheumatic drugs are also associated with HLA alleles. Understanding the role of HLA as the most important genetic factor relevant to RA susceptibility may help in determining its pathogenesis and pave the way to personalized medicine.