Sedative agents are widely used in the management of patients with head injury. These drugs can facilitate assisted ventilation and may provide useful reductions in cerebral oxygen demand. However, they may compromise cerebral oxygen delivery via their cardiovascular effects. In addition, individual sedative agents have specific and sometimes serious adverse effects. This review focuses on the different classes of sedative agents used in head injury, with a discussion of their role in the context of clinical pathophysiology. While there is no sedative that has all the desirable characteristics for an agent in this clinical setting, careful titration of dose, combination of agents, and a clear understanding of the pathophysiology and pharmacology of these agents will allow safe sedative administration in head injury.