Sepsis is a life-threatening organ dysfunction caused by a pathogenic microbial infection. Due to the complexity of the pathophysiological mechanism, the definition of its concept had undergone three major revisions since 1991. But it remains difficult to reach a broad consensus. Especially in the context of " Surviving Sepsis Campaign" , the high incidence and mortality, the lack of specific drugs, and many disappointing empirical treatment measures indicate that there is a long way to explore the pathogen-independent mediator responses in sepsis. As an important effector of the neuro-endocrine-immune regulatory network, the adrenal gland participates in the nonlinear and complex regulation of sepsis via responsive hormones by linking central stress signals and local microenvironmental responses. The early identification and replacement therapy of adrenal dysfunction and the re-recognition in the environment of sepsis disorder are undoubtedly the key aspects in the diagnosis and treatment of sepsis. Growing evidences of international clinical studies on adrenocortical hormones and pending recommendations in the past 30 years have further shown their therapeutic capacity. To this end, based on the 4P (preventive, predictive, personalized, participatory) medical model in translational medicine, this paper analyzes the diagnosis and treatment of adrenalcortical hormones from the definition and connotation of sepsis, and elaborates the theory of microenvironmental regulation of neuro-endocrine-immune network from the endogenous and exogenous adrenalcortical hormones. We try to further analyze the bottlenecks and confusion from the diagnosis and treatment of sepsis via adrenocortical hormones (type, dosage, single and combined treatment, time window), aiming to provide useful reference and enlightenment for the application of adrenocortical hormones in sepsis.