Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent years, the role of lipokines, which are lipid species predominantly secreted from adipose tissue that act as hormonal regulators in many metabolic tissues, has been an important area of research for obesity and diabetes. Previous studies have identified that these secreted lipids, including palmitoleate, 12,13-diHOME, and fatty acid–hydroxy–fatty acids (FAHFA) species, are important regulators of metabolism. Moreover, environmental factors that directly affect the secretion of lipokines such as diet, exercise, and exposure to cold temperatures constitute attractive therapeutic strategies, but the mechanisms that regulate lipokine stimulation have not been thoroughly reviewed. In this study, we will discuss the chemical characteristics of lipokines that position them as attractive targets for chronic disease treatment and prevention and the emerging roles of lipokines as regulators of inter-tissue communication. We will define the target tissues of lipokines, and explore the ability of lipokines to prevent or delay the onset and development of chronic diseases. Comprehensive understanding of the lipokine synthesis and lipokine-driven regulation of metabolic outcomes is instrumental for developing novel preventative and therapeutic strategies that harness adipose tissue-derived lipokines.