Recent field data have shown that the occupant protection in vehicle rear seats failed to keep pace with advances in the front seats likely due to the lack of advanced safety technologies. The objective of this study was to optimize advanced restraint systems for protecting rear seat occupants with a range of body sizes under different frontal crash pulses. Three series of sled tests (baseline tests, advanced restraint trial tests, and final tests), MADYMO model validations against a subset of the sled tests, and design optimizations using the validated models were conducted to investigate rear seat occupant protection with 4 Anthropomorphic Test Devices (ATDs) and 2 crash pulses. The sled tests and computer simulations were conducted with a variety of restraint systems including the baseline rear-seat 3-point belt, 3-point belts with a pre-tensioner, load limiter, dynamic locking tongue, 4-point belts, inflatable belts, Bag in Roof (BiR) concept, and Self Conforming Rear seat Air Bag (SCaRAB) concept. The results of the first two sled series demonstrated that the baseline 3-point belt system are associated with many injury measures exceeding injury assessment reference values (IARVs); showed the significance of crash pulse and occupant size in predicting injury risks; and verified the potential need of advanced restraint features for better protecting the rear-seat occupants. Good correlations between the tests and simulations were achieved through a combination of optimization and manual fine-tuning, as determined by a correlation method. Parametric simulations showed that optimized belt-only designs (3-point belt with pre-tensioner and load limiter) met all of the IARVs under the soft crash pulse but not the severe crash pulse, while the optimized belt and SCaRAB design met all the IARVs under both the soft and severe crash pulses. Two physical prototype restraint systems, namely an “advanced-belt only” design and an “advanced-belt and SCaRAB” design, were then tested in the final sled series. With the soft crash pulse, both advanced restraint systems were able to reduce all the injury measures below the IARVs for all four ATDs. Both advanced restraint systems also effectively reduced almost all the injury measures for all ATDs under the severe crash pulse, except for the THOR. The design with the advanced-belt and SCaRAB generally provided lower injury measures than those using the advanced belt-only design. This study highlighted the potential benefit of using advanced seatbelt and airbag systems for rear-seat occupant protection in frontal crashes.