The clinical course of most chronic diseases is associated with declined energy intake and nutrient-resistant progressive myopathy, characterized by accelerated proteolysis and impaired function. This anorexia/cachexia syndrome leads to deterioration of quality of life, and increased morbidity and mortality. The clinical efficacy of currently available therapeutic strategies is limited and more effective treatments are needed. Chronic systemic inflammation, triggered and sustained by cytokines, and increased oxidative stress contribute to the pathogenesis of the anorexia/cachexia syndrome. Carnitine and nicotine have recently been tested as immunomodulating and antioxidant agents. In particular, carnitine supplementation has been shown to reduce chronic inflammation and oxidative stress in hemodialysis patients and, in cancer patients, yielding to reduced fatigue and improved outcome. Nicotine is able to induce the anti-inflammatory activity of the vagus nerve. In animal models of sepsis and cancer, the nicotine-induced supplementation resulted in better protection of nutritional status and improved survival. In the continuous effort to develop more efficacious strategies against the anorexia/cachexia syndrome, carnitine and nicotine may represent a further therapeutic tool. More clinical studies are needed, however, before their use can be routinely suggested.