Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, multi-factorial 
disease sustained by environmental and genetic factors. These seem to be 
necessary but not sufficient in the disease development, nonetheless they can be 
responsible of different clinical pictures and response to therapy, and they can 
represent potential therapeutic targets. Several genes have been indicated so 
far in the pathogenesis of RA. The most important region is the Human Leukocyte 
Antigen (HLA) that contributes to approximately half of the genetic 
susceptibility for RA. The association seems to be stronger or specific for 
anti-citrullinated protein antibodies positive disease. Several alleles in the 
epitope-recognition part of the HLA molecule that show the highest association 
with RA susceptibility, also share a common string of amminoacid residues (the 
so-called shared-epitope hypothesis). Other variants in potentially pathogenic 
genes located in non-MHC regions have been implicated by recently performed 
genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, 
STAT4. Other polymorphisms seem to be responsible for more aggressive disease 
phenotype such as those located at TNF, IL-1, IL-6, IL-4, IL-5, OPN, PRF1. 
However, still nowadays, the genetic background of RA remains to be clearly 
depicted, and the efforts in the post-genomic era can bring to an estimation of 
the real likelihood of the genetic effect on RA. Finally, the discovery of new 
genes associated with the disease can be relevant in finding potential 
biomarkers, potentially useful in disease diagnosis and treatment.