In the article accompanying this editorial, a clinical trial of melatonin for the treatment of cancer cachexia is reported by Del Fabbro et al. Melatonin can be purchased over the counter or on the internet and thus is one of the many putative therapies for cancer cachexia that can be freely obtained by patients without consultation with a health care professional. The vast majority of such integrative therapies lack any evidence in support of their efficacy, other than anecdotal findings. The results of Del Fabbro et al are important because patients use these therapies at some expense and potentially some risk. The absence of either positive or negative findings at least means that patients are unlikely to experience any detriment from undertaking melatonin therapy, and at best these placebo-controlled and double-blinded findings would discourage their future use. Cancer anorexia in particular is subject to substantial placebo effects, and it cannot be underestimated how important it is to conduct well-stratified, randomized, blinded, and controlled trials. The context of the Del Fabbro et al study was within a program where there was excellent attention to pain and symptom management while patients were evaluated for eligibility and eventually included in the trial. This means that the standard of care for symptom management was not as much of a wild card as they might otherwise have been, especially as in multicenter studies with disparate standards of care. The melatonin story is a good example of how optimistic results in open label and uncontrolled trials are deflated by the first controlled investigation. Preclinical studies may also inflate the hopes for a new cachexia therapy. On the surface of it, the evidence in animal models sounds quite compelling for pleiotropic beneficial actions of melatonin on appetite, intestinal transit, nutrient absorption, inflammation, and even antitumor effects. However, several of these findings were observed in healthy animals, in nonmalignant disease or a single cancer model. Indeed, there was no evidence as to whether melatonin has these effects in the presence of tumor and systemic inflammation, or whether it would be equally effective at early, intermediate, and late stages of cachexia. During the time the study in the current report was developed and completed, there has been a thoughtful reconsideration of cancer cachexia by within the clinical cancer research community. This introspection has in part been motivated by the fact that there have been approximately 100 randomized clinical investigations of therapies for cancer cachexia and anorexia, yet many of them, like the present one, have been negative and have not resulted in approved therapies. Research on the underlying biology of cancer cachexia has expanded dramatically, especially in relation to its characteristic pronounced catabolism of skeletal muscle. Cachexia is now the subject of a series of biannual international conferences, a journal, and a Society on Cachexia and Wasting Disorders. International consensus groups have convened to address lack of consistency in defining cachexia, in the use of diagnostic criteria for cachexia and in the design of cachexia-related clinical trials. These consensus building efforts herald a paradigm shift in the design of clinical trials on cancer-associated cachexia. Here are some of the new concepts that current and future cancer cachexia clinical trials are incorporating into their designs: