The treatment of complicated intra-abdominal infections continues to challenge physicians, primarily because of the polymicrobial nature of these infections coupled with the high risk of complications and even death among the more severe patients. The initial selection of antimicrobial therapy for treatment of nosocomial intraabdominal infections is extremely important because an association has been shown between inappropriate empiric antimicrobial therapy and delayed clinical resolution, increased length of hospital stay, and an increased risk of mortality. Moreover, it is becoming more frequent for isolates recovered from patients to possess multiple resistance factors (e.g., extended-spectrum beta-lactamases [ESBLs], vancomycin-resistant enterococci [VRE]). Therefore, when selecting empiric antimicrobial therapy, the physician must consider the likelihood of encountering one of these difficult-to-treat isolates and select an agent or agents with anticipated activity against such organisms. Here, we discuss the merits and limitations of empiric therapy for nosocomial intra-abdominal infections, review the current guidelines for treatment, and discuss the therapeutic options currently available.