With the advent of biological therapies, considerable progress has been made in the treatment of rheumatoid arthritis (RA). These revolutionary therapies owe their origin to the role that cytokines play in the pathophysiology of the disease and are best exemplified by the wide use of tumor necrosis factor (TNF) blockade. The identification of additional pro-inflammatory factors and an understanding of their effector function now offer major possibilities for the generation of additional novel biological therapeutics to address unmet clinical needs. Such interventions will ideally fulfill several of the following criteria: control of inflammation, modulation of underlying immune dysfunction by promoting the reestablishment of immune tolerance, protection of targeted tissues such as bone and cartilage, and preservation of host immune capability to avoid profound immune suppression and amelioration of co-morbidity associated with underlying RA. The identification and characterization of the intracellular signaling pathways, in particular, the mitogen-activated protein kinase pathway, the nuclear factor-κB pathway and the cross-talk between these pathways offer several potential therapeutic opportunities. This review will provide an update on cytokine activities and signal transduction pathways that represent, in our opinion, optimal utility as future therapeutic targets.