Background: Glucocorticoids such as cortisol are important regulators of fuel metabolism during starvation and stress. Chronic glucocorticoid excess induces obesity with multiple features of the metabolic syndrome. Objective: In this article, we review the importance of glucocorticoids in metabolic syndrome and the approaches that have been explored to reduce glucocorticoid action as the basis for novel therapy of Type 2 diabetes and obesity. Method: We focus on the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which amplifies glucocorticoid concentrations in key metabolic tissues including liver and adipose tissue. Results/conclusion: Several 11β-HSD1 inhibitors are in late preclinical or early clinical development and we review here the properties of the class leaders and their potential as the next generation of drugs with multiple benefits in metabolic syndrome.