Corticosteroid-binding globulin (CBG) is a plasma glycoprotein discovered more than 60 years ago for its high-affinity for glucocorticoids. Although its molecular structure and its biochemical properties have been described, its various biological roles and its importance are not yet fully understood. This review focuses first on studies that have used no-hypothesis-driven genetic approaches in animal models to reveal the higher than expected importance of CBG in particular in glucocorticoid stress responses. Then the dissection of some CBG physiological roles in an animal model of genetic CBG deficiency is reported. Finally, studies on the role of CBG genetic variability in human obesity traits are reviewed and discussed.