Metabolic homeostasis emerges from the complex, multidirectional crosstalk between key metabolic tissues including adipose tissue, liver, and skeletal muscle. This crosstalk, traditionally mediated by hormones and metabolites, becomes dysregulated in human diseases such as obesity and diabetes. Extracellular vesicles (EVs; including exosomes) are circulating, cell-derived nanoparticles containing proteins and nucleic acids that interact with and modify local and distant cellular targets. Accumulating evidence, reviewed herein, supports a role for extracellular vesicles in obesity-associated metabolic disturbance, particularly the local and systemic inflammation characteristic of adipose and hepatic stress. As the practical and conceptual challenges facing the field are tackled, this emerging and versatile mode of intercellular communication may afford valuable insights and therapeutic opportunities in combatting these major threats to modern human health.