Serotonin is a well-known neurotransmitter that is synthesized from the amino acid, tryptophan. To date, more than 14 different serotonin receptors have been discovered; they exist universally in our body and enable diverse biological functions in different organs. Central serotonin regulates mood and behavior, and impacts the systemic energy balance by decreasing appetite. A number of drugs that modulate central serotonin function (e.g., fenfluramine, sibutramine and lorcaserin) were approved and used as anti-obesity drugs, but then later withdrawn due to adverse cardiovascular and carcinogenic effects. Over the past decade, the role of peripheral serotonin in regulating systemic energy metabolism has been extensively explored using tissue-specific knockout animal models. By inhibiting the action of serotonin in liver and adipose tissues, hepatic steatosis was improved and lipid accumulation was mitigated, respectively. Recent findings show that modulation of the serotonergic system is a promising therapeutic target for metabolic diseases. This review summarizes the role of serotonin in regulating energy metabolism in different organs, and discusses the potential of serotonin modulation for treating metabolic diseases.