Rheumatoid arthritis (RA) is a systemic disease with polyarticular manifestation of chronic inflammation in the knees and small joints of hand and feet. The current systemic anti-tumor necrosis factor (TNF)-alpha therapies with biologics ameliorate disease in 60% to 70% of RA patients. However, biologics must be given systemically in relatively high dosages to achieve constant therapeutic levels in the joints, and side effects have been reported. To this end, local gene delivery can provide an alternative approach to achieve high, long-term expression of biologics, optimizing the therapeutic efficacy and minimizing systemic exposure. Evidence from animal models convincingly supports the application of local gene therapy in rheumatoid arthritis, but preclinical studies remain necessary to evaluate the merge of cell-specific targeting, viral vector development, and disease-regulated transgene expression to optimize efficacy and safety.