Rheumatoid arthritis (RA) is an autoimmune disease with an unclear pathogenic mechanism. However, it has been proven that the key underlying risk factor is a genetic predisposition. Association studies of the HLA-DRB1 gene clearly indicate its importance in RA morbidity. This review presents the current state of knowledge on the impact of HLA-DRB1 gene, functioning both as a component of the patient's genome and as an environmental risk factor. The impact of known HLA-DRB1 risk variants on the specific structure of the polymorphic HLA-DR molecule, and epitope binding affinity, is presented. The issues of the potential influence of HLA-DRB1 on the occurrence of non-articular disease manifestations and response to treatment are also discussed. A deeper understanding of the role of the HLA-DRB1 gene is essential to explore the complex nature of RA, which is a result of multiple contributing factors, including genetic, epigenetic and environmental factors. It also creates new opportunities to develop modern and personalized forms of therapy.