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Septic shock is a leading cause of mortality in intensive care units throughout the world. While this disease state represents a highly complex pathophysiology involving numerous organ systems, the early approach to care includes adequate hemodynamic support traditionally achieved via infusions of vasoactive medications after adequate fluid resuscitation. Relative adrenal and vasopressin deficiencies are a common feature of septic shock that contribute to impaired hemodynamics. Hydrocortisone and vasopressin are endocrine system hormone analogues that target the acute neuroendocrine imbalance associated with septic shock. This clinically focused annotated review describes the pathophysiological mechanisms behind their use and explores the potential clinical roles of early administration and synergy when combined.