There is increasing evidence that distinct signaling and effector pathways in the rheumatoid synovium result in a cascade of pathophysiologic events. These interactions, which finally lead to progressive joint destruction, are different from all other joint diseases in numerous aspects. As outlined in this review, molecular biology techniques allow detection of key pathways ranging from external stimuli to subcellular gene regulation mechanisms operative in various cells within the rheumatoid synovium. To alter these pathways, inhibitory factors need to be applied to these “hot zones” for an extended period, which can be achieved either by repeated drug administration or by local synthesis using genetically altered synovial cells. Both adenovirus and retroviral constructs, as well as ex vivo and in vivo strategies, can be used for gene transfer into these cells, and routine delivery of “protective” genes into the affected joints might be achieved within the next decade.