Improving the predictability of airline schedules in the National Airspace System (NAS) has been a constant endeavor, particularly as system delays grow with ever-increasing demand. Airline schedules need to be resistant to perturbations in the system including Ground Delay Programs (GDPs) and inclement weather. The strategic search heuristic proposed in this dissertation significantly improves airline schedule reliability by assigning airport departure and arrival slots to each flight in the schedule across a network of airports. This is performed using a multi-objective optimization approach that is primarily based on historical flight and taxi times but also includes certain airline, airport, and FAA priorities. The intent of this algorithm is to produce a more reliable, robust schedule that operates in today's environment as well as tomorrow's 4-Dimensional Trajectory Controlled system as described the FAA's Next Generation ATM system (NextGen). This novel airline schedule optimization approach is implemented using a multi-objective evolutionary algorithm which is capable of incorporating limited airport capacities. The core of the fitness function is an extensive database of historic operating times for flight and ground operations collected over a two year period based on ASDI and BTS data. Empirical distributions based on this data reflect the probability that flights encounter various flight and taxi times. The fitness function also adds the ability to define priorities for certain flights based on aircraft size, flight time, and airline usage. The algorithm is applied to airline schedules for two primary US airports: Chicago O'Hare and Atlanta Hartsfield-Jackson. The effects of this multi-objective schedule optimization are evaluated in a variety of scenarios including periods of high, medium, and low demand. The schedules generated by the optimization algorithm were evaluated using a simple queuing simulation model implemented in AnyLogic. The scenarios were simulated in AnyLogic using two basic setups: (1) using modes of flight and taxi times that reflect highly predictable 4-Dimensional Trajectory Control operations and (2) using full distributions of flight and taxi times reflecting current day operations. The simulation analysis showed significant improvements in reliability as measured by the mean square difference (MSD) of filed versus simulated flight arrival and departure times. Arrivals showed the most consistent improvements of up to 80% in on-time performance (OTP). Departures showed reduced overall improvements, particularly when the optimization was performed without the consideration of airport capacity. The 4-Dimensional Trajectory Control environment more than doubled the on-time performance of departures over the current day, more chaotic scenarios. This research shows that airline schedule reliability can be significantly improved over a network of airports using historical flight and taxi time data. It also provides for a mechanism to prioritize flights based on various airline, airport, and ATC goals. The algorithm is shown to work in today's environment as well as tomorrow's NextGen 4-Dimensional Trajectory Control setup.