Background: Management of complicated intra-abdominal infections involves invasive procedures for control of the source of the infection and antimicrobial therapy directed against gram-negative and anaerobic pathogens. Application of these management principles to the individual patient is essential to optimize the patient's chances for recovery, while also avoiding unnecessary therapy that may have no clinical benefits, or that may carry risk. Methods: Based on a review of the literature, treatment guidelines, and expert opinion, the challenges of managing patients with complicated intra-abdominal infections are summarized using a patient stratification approach: "Lower risk" of treatment failure and death vs. "higher risk." Results: Risk factors for treatment failure and death can be grouped into several categories, including the patient's pre-existing medical comorbidities and physiological response to the infection, the extent of the intra-abdominal infection, and the presence of specific pathogenic microorganisms. These latter factors may be more useful than the Acute Physiology and Chronic Health Evaluation (APACHE) II score in evaluating specific management strategies for patients with complicated intra-abdominal infections. The principal goal of treatment in lower-risk patients is to avoid morbidity related to source control procedures and antimicrobial therapy. Limitation of the scope of source control procedures and utilization of short-duration, narrow-spectrum, low-toxicity antimicrobial regimens is advisable to avoid adverse drug reactions and selection of resistant organisms. For higher-risk patients, the goal is to develop improved management modalities, so that morbidity and mortality are reduced. The recommended approach for higher-risk patients is to identify the most appropriate source control procedure and antimicrobial therapy, as dictated by the patient's specific risk factors, and to utilize the optimal tools of critical care medicine to treat these critically ill, septic patients. The emergence of bacterial resistance also must be considered when selecting antimicrobial therapy for both low risk and high risk patients with intra-abdominal infections. Because aminoglycoside regimens are becoming less favored, and optimal therapeutic strategies have not been standardized, the use of new treatment options (e.g., tigecycline) may be valuable when managing patients with intra-abdominal infections. especially for resistant isolates. Conclusions: The management of lower-risk patients with intra-abdominal infections is distinct compared with patients at higher risk due to compromised physiological status, extent of intra-abdominal infection, or presence of nosocomial pathogens associated with higher-risk patients. Carefully designed, multidisciplinary-sponsored, clinical trials in patients with specific clinical risk factors are needed to better assess the role of various antimicrobial regimens in the treatment of higher-risk patients with intra-abdominal infections.