Progress in understanding the cellular and molecular mechanisms of rheumatoid arthritis (RA), together with the availability of new therapies, has changed the way we think about RA. The paradigm shift in RA therapy has been from controlling symptoms to controlling the disease process with the abrogation of inflammation. Challenges that are still unresolved include the issues in disease prevention, treatment specificity to restore tolerance, approaches to facilitate tissue repair, and treatment optimization to fit the individual patient's disease phenotype and comorbidity context. This review summarizes the pathogenesis-related rationales for the current therapeutic strategies in RA and for emerging therapies and potential approaches to restoring immune tolerance in RA.