A better understanding of the mechanisms that contribute to the resistance of synovial macrophages and fibroblasts to apoptosis will not only provide better insights into the mechanisms contributing to the perpetuation of rheumatoid arthritis (RA) but will also help identify targets for the development of novel, more effective, and long-lasting therapies for the treatment of patients with RA. To avoid toxicity, such as the induction of apoptosis of critical organs, the mechanisms by which these molecules are targeted and therapy delivered must be carefully selected, using the insights obtained from studies characterizing the mechanisms that promote chronic inflammation.