Traumatic knee injuries frequently involve the disruption of multiple ligaments, such as a complete tear of the medial collateral ligament (MCL) together with a rupture of the anterior cruciate ligament (ACL) (Miyasaka, K., D. M. Daniel, M. L. Stone, and P. Hirshman. Am. J. Knee Surg. 4:3-8, 1991). Despite the high incidence, clinical management of this type of injury is still debated. Laboratory studies have shown that the ACL and MCL share the responsibility of stabilizing the knee, especially in response to valgus and other rotatory torques as well as anterior tibial loads (Inoue, M., E. McGurk-Burleson, J. M. Hollis, and S. L-Y. Woo. Am. J. Sports Med. 15:15-21, 1987; Kanamori, A., M. Sakane, J. Zeminski, T. W. Rudy, and S. L-Y. Woo. J. Ortho. Sci. 5:567-571, 2000; Ma, C. B., C. D. Papageogiou, R. E. Debski, and S. L. Woo. Acta Orthop. Scand. 71:387-393, 2000; Sakane, M., G. A. Livesay, R. J. Fox, T. W. Rudy, T. J. Runco, and S. L-Y. Woo. Knee Surg. Sports Traumatol. Arthrosc. 7:93-97, 1999). When one structure is deficient, the force in the other increases significantly to compensate. The injured ACL does not heal and requires surgical replacement by tissue grafts. On the other hand, after an isolated MCL tear or in a combined MCL and ACL injury, the MCL can heal spontaneously without surgical intervention and can function well in most cases. Nevertheless, the biomechanical and biochemical properties as well as the histomorphological appearance of the healing MCL are substantially different to those of normal tissue (Bray, R. C., D. J. Butterwick, M. R. Daschak, and J. V. Tyberg. J. Orthop. Res. 14:618-625, 1996; Loitz-Ramage, B. J., C. B. Frank, and N. G. Shrive. Clin. Orthop.:272-280, 1997; Weiss, J. A., S. L-Y. Woo, K. J. Ohland, S. Horibe, and P. O. Newton. J. Orthop. Res. 9:516-528, 1991). In an effort to improve the outcome of injuries to these and other ligaments, therapeutic strategies associated with improving biomechanical, biochemical, and histomorphological properties of ligaments have been investigated in recent years. These therapeutic strategies include growth factor stimulation (Conti, N. A., and L. E. Dahners. Presented at Orthopaedic Research Society, San Francisco, CA; Deie, M., T. Marui, C. R. Allen, K. A. Hildebrand, H. I. Georgescu, et al. Mech. Ageing Dev. 97:121-130, 1997), cell therapy (Menetrey, J., C. Kasemkijwattana, C. S. Day, P. Bosch, F. H. Fu, et al. Tissue Eng. 5:435-442, 1999; Watanabe, N., S. L-Y. Woo, C. Papageorgiou, C. Celechovsky, and S. Takai. Microsc. Res. Tech. 58:39-44, 2002), as well as gene stherapy (Nakamura N., D. A. Hart, R. S. Boorman, Y. Kaneda, N. G. Shrive, et al. J. Orthop. Res. 18:517-523, 2000; Shimomura, T., F. Jia, C. Niyibizi, and S. L-Y. Woo. Connect. Tissue Res.:2003). The knowledge gained by studying these therapeutic strategies could potentially be applied to other ligaments and tendons. In this article, antisense gene therapy to alter gene expression by using antisense oligonucleotides will be examined as a possible solution.