Sepsis in the intensive care unit (ICU) presents a great challenge to any critical care clinician. Patients admitted to the ICU are especially vulnerable to sepsis due to the nature of the underlying pathology that warranted admission to the ICU and deranged physiological function coupled with invasive procedures. Nosocomial infections are common in patients admitted to the ICU, and with these infections come the burden of multidrug-resistant organisms. Antimicrobial resistance (AMR) is now a global emergency that warrants the attention of every health-care professional. AMR has escalated to epic proportions and solutions to this problem are now a matter of "life and death." The ICU also represents the "breeding ground" of antibiotic-resistant organisms due to the high broad-spectrum antibiotic consumption. Many would argue that broad-spectrum antimicrobials are overprescribed in this patient population, but do all patients admitted to the ICU warrant such therapy? Is there evidence that narrower-spectrum antimicrobial agents can be employed in specific ICU populations coupled with surveillance strategies? The aims of this review are to focus on strategies with the aim of optimizing antimicrobial use within ICUs, and to highlight the importance of differentiating ICU populations with regard to the use of antimicrobial agents.