With the advent of biological therapies, considerable advances have been achieved in the treatment of inflammatory arthritis. These have arisen primarily from studies elucidating mechanisms of pathophysiology and are best exemplified in the wide use of tumour necrosis factor (TNF) blockade in several rheumatic diseases. The identification of additional pro-inflammatory factors in rheumatic diseases and an understanding of their effector function, now offers major possibilities for the generation of novel therapeutics. To address unmet clinical need, such interventions will ideally fulfil several of the following criteria: (1) control of inflammation, (2) modulation of underlying immune dysfunction - promoting the re-establishment of immune tolerance, (3) protection of targeted tissues such as bone and cartilage - this should encompass promoting healing of previously damaged tissues, (4) preservation of host immune capability - to avoid profound immune suppression and (5) amelioration of co-morbidity associated with underlying inflammatory arthritis. This short review will consider those novel cytokine activities that represent optimal utility as therapeutic targets. Since we wish to reflect the current predominant research effort, we will focus primarily on rheumatoid arthritis (RA) based studies.