Significance Obesity is a major health threat of the twenty-first century, impacting individual patients and healthcare expenditure. Due to safety concerns, few antiobesity treatments with only moderate effect remain on the market. The ghrelin receptor is an attractive target for the development of novel antiobesity drugs, since ghrelin increases both fat accumulation and food intake. However, ghrelin also modulates a variety of additional physiological functions. Thus, drugs targeting the ghrelin receptor may induce unacceptable side effects and have limited clinical use. We demonstrate that biased ligands, which selectively activate only a subset of the molecular signaling pathways, may be powerful tools to obtain drugs that efficaciously reduce body weight without inducing adverse effects by selectively modulating appetite and energy expenditure.