Methods and devices are provided for activating brown adipose tissue with targeted substance delivery. Generally, the methods and devices can activate BAT to increase thermogenesis, e.g., increase heat production in the patient, which over time can lead to weight loss and/or improved metabolic function. In one embodiment, a chemical configured to stimulate nerves that activate the BAT and/or to stimulate brown adipocytes directly can be delivered to a patient, thereby increasing thermogenesis in the BAT and inducing weight loss and/or improved metabolic function through energy expenditure. The chemical can be delivered to the patient locally and/or systemically to stimulate the nerves and/or the brown adipocytes.