Gene therapy is not for the faint of heart. Since its launch in 1989 [1], human gene therapy has been variously cast as visionary, feckless, a panacea and a dangerous folly. One of its pioneers is in jail, and another was sued successfully in civil court following the death of a clinical trial subject. Skeptics like to point out that it has killed approximately as many people as it has cured and, apart from two cancer gene therapies approved recently in China, there is little to show for nearly two decades of promises and expensive research. Against these headwinds, arthritis gene therapy has made laudable progress. Proof of principle is well established in animal models, and a small number of clinical trials have been implemented (Table 1). However, we have reached the stage of diminishing returns with preclinical research. Pivotal clinical trials are needed to maintain momentum and confirm promise in human disease [2]. These will require a considerable injection of funding, without which research will stagnate and become largely condemned to re-inventing the wheel in animal models. Arthritis gene therapy emerged in the early 1990s (Figure 1) and made quite rapid progress, leading, within a few years, to proof of concept in animal models of rheumatoid arthritis and osteoarthritis, and a Phase I clinical trial – remarkable achievements for a new area of research. As reflected in the publication history shown in Figure 1, the number of investigators remains limited, with approximately 30 papers appearing in the refereed literature each year at a remarkably constant rate since 1999. The fact that almost half of these publications are review articles is telling. Arthritis was the subject of the first human gene-therapy protocol for a nonlethal disease [3], and consequently attracted much scrutiny from the regulatory agencies. The data from this trial confirmed that genes could be safely transferred to human joints and expressed within them [4]. Moreover, in a similar small, German study, each of two subjects treated with this gene therapy appeared to mount a clinical response, one of them dramatically so [5] [Wehling et al., Unpublished Data]. Nevertheless, the ex vivo, retrovirus-based approach used in these two studies is unlikely to find wide clinical application; ex vivo gene transfer using autologous cell culture is too cumbersome and costly, and concerns regarding insertional mutagenesis with retrovirus vectors have resurfaced. Subsequent clinical trials (Table 1) based on this approach have used allogeneic cells lines to reduce costs and, in one case, irradiation of cells to prevent cell division and thus tumorigenicity. In the search for an efficient vector that can be introduced safely into joints by intra-articular injection, most investigators have converged on adeno-associated virus (AAV). Recombinant AAV has risen in popularity as a gene therapy vector because it is perceived to be safe and new technologies permit easier production of clinical-grade material [6]. Wild-type AAV causes no known disease and recombinant AAV vectors have been used safely in gene therapy trials of a number of single-gene disorders, as well as Parkinson’s disease, Alzheimer’s disease and cancer. Two large Phase III trials for prostate cancer using AAV are underway, and orphan drug status has been granted by the EU for AAV-mediated gene therapy for familial lipoprotein lipase deficiency.