Obesity causes an imbalance in the expression and secretion of several organokines, which in turn contributes to the development of metabolic disorders such as type 2 diabetes mellitus. Organokines are produced by corresponding organs and affect systemic metabolic homeostasis. Diverse organokines play a crucial role in the communication between adipose tissue, skeletal muscle and other organs. In this review, we discuss the biological properties of specific organokines such as adipokines, hepatokines, and myokines. We also highlight the cumulative roles and crosstalk of organokines in obesity-related T2DM. Moreover, we attempt to identify the diagnostic and therapeutic potential of obesity-related T2DM from the perspective of organokines.