Metabolic flexibility is the ability to adapt to physiological and environmental changes in metabolic demand. Irisin was originally discovered as an exercise-induced myokine involved in fat browning. In this review, we summarize emerging evidence for the roles of irisin in regulating glucose metabolism and insulin sensitivity in skeletal muscle, neuroplasticity and satiety in central nervous system, β cell function and insulin secretion in the pancreas, bone remodeling, and adipose tissue function, which together orchestrate whole-body metabolic flexibility. Irisin is a key communicating mediator between skeletal muscle and other organs, and its manipulation could be a promising therapeutic strategy for treating obesity and related metabolic disorders.