Advances in molecular and cellular biology have identified a wide variety of proteins including targeted cytokine inhibitors, immunomodulatory proteins, cytotoxic mediators, angiogenesis inhibitors, and intracellular signalling molecules that could be of great benefit in the treatment of chronic joint diseases, such as osteo- and rheumatoid arthritis. Unfortunately, protein-based drugs are difficult to administer effectively. They have a high rate of turnover, requiring frequent readministration, and exposure in non-diseased tissue can lead to serious side effects. Gene transfer technologies offer methods to enhance the efficacy of protein-based therapies, enabling the body to produce these molecules locally at elevated levels for extended periods. The proof of concept of gene therapies for arthritis has been exhaustively demonstrated in multiple laboratories and in numerous animal models. This review attempts to condense these studies and to discuss the relative benefits and limitations of the methods proposed and to discuss the challenges toward translating these technologies into clinical realities.