Beta-lactam antibiotics are used for the treatment of various infections such as intra-abdominal infections and bacterial meningitis. Beta-lactams act at the infection site and their antibacterial effects relate to the exposure time during which the drug concentrations remain above the minimum inhibitory concentration for bacteria (T>MIC). The penetration into and exposure of beta-lactams at the target sites, such as the abdominal cavity and the cerebrospinal space, are therefore considered to be good indicators of their efficacies. However, earlier clinical research has focused primary on the drug concentrations in plasma. We therefore examined the pharmacokinetics-pharmacodynamics of beta-lactams at the target sites, and analyzed them using a population pharmacokinetic modeling and statistical technique called Monte Carlo simulation. This review summarizes our recent findings on carbapenem and cephem antibiotics in peritoneal and cerebrospinal fluids, and our new approaches to personalize and optimize beta-lactam dosing regimens based on their site-specific pharmacokinetic-pharmacodynamic profiles.