Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with both genetic and environmental factors. The DRB1 gene at the human leukocyte antigen (HLA) locus of chromosome 6p21.3 was the first genetic factor associated with RA to be identified in the 1980s; however, identification of causative genes other than those at the HLA locus has been challenging for geneticists because of the strong linkage disequilibrium in this locus and the non-Mendelian inheritance pattern of RA. Recent advances in high-throughput single nucleotide polymorphism genotyping technologies and bioinformatic analysis tools have facilitated the identification of positive associations of hundreds of genes with RA using family-based linkage analyses and genome wide association studies. Some of the RA associated genes at non-HLA loci are as follows: PADI4, PTPN22, STAT4, and TNFAIP3. In this paper, we describe the pathological mechanisms mediated by these genes. In addition, we review results of previous genetic studies of RA and future challenges in connecting the dots of missing heritability in the post-genome-wide association study era.