Articular cartilage defects are an unsolved problem in clinical orthopaedics as such lesions often do not heal on themselves and no treatment leads to full and long-term regeneration. Although gene therapy is an attractive concept to treat cartilage damage, current research indicates that an adaptation of gene transfer techniques to the problem of a circumscribed defect is required in order to successfully implement this approach. In particular, the local availability of the therapeutic gene product in the defects is desirable. Current strategies aim at inducing chondrogenic pathways in the repair tissue that fills the defect, including the stimulation of chondrocyte proliferation, maturation, and matrix synthesis via direct or indirect approaches. A better understanding of the basic scientific aspects of cartilage defect repair, the identification of new targets, and the development of improved delivery techniques may allow to translate gene therapy for cartilage defects in the clinics. The first experimental steps provide reason for cautious optimism.