Rheumatoid arthritis is a complex autoimmune disease affecting up to 1% of the population, causing a disabling inflammatory arthritis. The disease has two clinical similar subsets: autoantibody positive or seropositive disease, and autoantibody or seronegative disease. Recent advances in high-throughout SNP genotyping has resulted in the identification of >100 risk loci, in addition to well-known associations at the MHC. However, understanding the link between genetic loci and disease mechanism, is contingent on investigators identifying causal alleles and elucidating how they function to modify disease susceptibility. Furthermore, the mechanistic relationship between the seropositive and seronegative rheumatoid arthritis clinical subsets is still unclear. We are now just starting to make progress in this direction. Here we present recent work on (1) efforts to localize MHC effects to functional amino acid sites within HLA genes, (2) methodological advances to connect non-MHC loci to functional alleles that influence gene regulation in a cell-specific manner, and (3) how genetics is giving us a clear picture on the heterogeneity of the genetic bases of the two clinically similar conditions of seronegative and seropositive rheumatoid arthritis.