Trauma remains a leading cause of morbidity and mortality among all age groups in the United States. Hemorrhagic shock and traumatic brain injury (TBI) are major causes of preventable death in trauma. Initial treatment involves fluid resuscitation to improve the intravascular volume. Although crystalloids may provide volume expansion, they do not have any pro-survival properties. Furthermore, aggressive fluid resuscitation can provoke a severe inflammatory response and worsen clinical outcomes. Due to logistical constraints, however, definitive resuscitation with blood products is often not feasible in the prehospital setting-highlighting the importance of adjunctive therapies. In recent years, histone deacetylase inhibitors (HDACis) have shown promise as pharmacologic agents for use in both trauma and sepsis. In this review, we discuss the role of histone deacetylases (HDACs) and pharmacologic agents that inhibit them (HDACis). We also highlight the therapeutic effects and mechanisms of action of HDACis in hemorrhagic shock, TBI, polytrauma, and sepsis. With further investigation and translation, HDACis have the potential to be a high-impact adjunctive therapy to traditional resuscitation.