The investigation of genetic factors affecting the development or severity of rheumatoid arthritis may give new insights into the pathways involved in disease pathogenesis and lead to the identification of novel therapeutic targets. Recently, several novel approaches have been used in the attempt to unravel the complex association of rheumatoid arthritis with the human leukocyte antigen ( HLA ) gene region. It is clear that non-HLA genes are also involved in disease pathogenesis, and identifying them remains a challenge. In the past year, considerable headway has been made in this field, and some interesting strategies have been used. This review summarizes the results of many of the HLA and non-HLA studies and tries to draw lessons from the investigation of genetic susceptibility factors in other complex diseases.