Prescription of antibiotics in the critically ill is a complex process. It requires consideration of the likely causative organism/s, an appreciation of the underlying pathophysiological state and how this dynamic process influences drug distribution, metabolism and elimination. Associated organ dysfunction, fluid shifts and altered immune status are common, and each can influence the efficacy of many antimicrobial agents. This chapter will focus on the prescription of antibiotics commonly used in the treatment of critically ill patients with severe sepsis or septic shock. Early appropriate antimicrobial therapy remains the cornerstone of successful treatment in this group (Kollef et al. 1999; Ibrahim et al. 2000; Garnacho-Montero et al. 2003; Valles et al. 2003). Pharmacokinetic and pharmacodynamic principles will be reviewed, with the aim to optimize dosing and improve outcome. There are similar considerations concerning the use of antifungal and possibly antiviral agents in the critically ill; however, a wider discussion of these agents is beyond the scope of this chapter.