Effective management of Rheumatoid Arthritis (RA) is being hampered by the difficulties for its early diagnosis and the heterogeneity of the disease. Although early intervention can result in disease remission, it requires early diagnosis, and current diagnostic tests are not sufficiently accurate or sensitive in the early stages of RA. Therefore, research efforts are increasingly focused on gaining knowledge about RA pathogenesis, and also on the discovery of novel biological markers that enable early diagnosis and stratification of the disease, and thus the implementation of targeted therapies. Ongoing research includes the emergence of novel approaches for the characterization of molecules that play a role in RA, such as genomic, proteomic and metabolomic technologies. These techniques, coupled with sophisticated statistical methods, permit the simultaneous analysis of multiple targets, and have become very powerful tools in RA research both for etiopathogenesis studies and biomarker discovery. It is believed that proteomics will soon provide a much-needed novel therapeutic approach to treating RA. This chapter will focus on the utility of Proteomics in RA research to enable a better understanding of the disease process, and to provide novel protein biomarkers useful for early diagnosis, prognosis and the application of tailored treatments.