Cefepime is commonly used in the intensive care unit (ICU) to treat bacterial infections. The time during which the free cefepime concentration is above the MIC (fT>MIC) should be optimized to increase the efficacy of the regimen. We aim to optimize the exposure of cefepime in ICU patients by using population pharmacokinetic (PK) modeling and simulations. Two data sets were included in this study. The first was a prospective study of pediatric patients who received cefepime at 50 mg/kg of body weight and had extensive PK sampling. The second study comprised retrospective data for adult ICU patients admitted to UF Health Shands Hospital who received cefepime and had their cefepime concentrations measured. The population PK model was developed, and simulations were performed, using Pmetrics. The target exposures were 100% fT>MIC and 100% fT>4×MIC The studies included a total of 266 patients, and the mean ages were 3.9 years in the pediatric group and 55 years in adult group. More than half of the patients were males. The mean (standard deviation [SD]) creatinine clearance (CrCl) was 125 (93) ml/min. The mean (SD) daily dose for adults was 4.9 (1.6) g. Cefepime was well described by a two-compartment model with weight as a covariate on the volume of distribution and elimination rate constant (kel), and CrCl and age group as covariates on kel At a MIC of 8 mg/liter, a cefepime loading dose of 4 g as an extended infusion followed by a 6-g continuous infusion was needed for good target attainment. In conclusion, prolonged or continuous infusions will be needed to achieve optimal cefepime exposure for ICU patients. Given the observed variability, therapeutic drug monitoring can help individualize therapy.