Glucocorticoids (GCs) are steroid hormones characterized by their anti-inflammatory and immunosuppressive nature. Although GCs are very commonly prescribed, in several diseases, including sepsis, their clinical treatment is hampered by side effects and by the occurrence of glucocorticoid resistance (GCR). Sepsis is defined as a life-threatening organ dysfunction, initiated by a dysregulated systemic host response to infections. With at least 19 million cases per year and a lethality rate of about 25%, sepsis is one of the most urgent unmet medical needs. The gut is critically affected during sepsis and is considered as a driving force in this disease. Despite there is no effective treatment for sepsis, pre-clinical studies show promising results by preserving or restoring gut integrity. Since GC treatment reveals therapeutic effects in Crohn's disease (CD) and in pre-clinical sepsis models, we hypothesize that targeting GCs to the gut or stimulating local GC production in the gut forms an interesting strategy for sepsis treatment. According to recent findings that show that dimerization of the glucocorticoid receptor (GR) is essential in inducing anti-inflammatory effects in pre-clinical sepsis models, we predict that new generation GCs that selectively dimerize the GR, can therefore positively affect the outcome of sepsis treatment. Copyright © 2020 Elsevier Ltd. All rights reserved.