Underlying the pathogenesis of chronic disease is the state of oxidative stress. Oxidative stress is an imbalance in oxidant and antioxidant levels. If an overproduction of oxidants overwhelms the antioxidant defenses, oxidative damage of cells, tissues, and organs ensues. In some cases, oxidative stress is assigned a causal role in disease pathogenesis, whereas in others the link is less certain. Along with underlying oxidative stress, chronic disease is often accompanied by muscle wasting. It has been hypothesized that catabolic programs leading to muscle wasting are mediated by oxidative stress. In cases where disease is localized to the muscle, this concept is easy to appreciate. Transmission of oxidative stress from diseased remote organs to skeletal muscle is thought to be mediated by humoral factors such as inflammatory cytokines. This review examines the relationship between oxidative stress, chronic disease, and muscle wasting, and the mechanisms by which oxidative stress acts as a catabolic signal.