The sustainability of megacities and the ecosystems they influence are critical for ensuring quality of life and environment throughout the world. This sustainability requires infrastructure systems that provide a good and equitable quality of life, and a balance between consumption, disposal, and environmental capacity. Megacities must be strengthened and prepared to resist all hazards that may threaten them. Megacities function as a mega-system made up of many independent subsystems that have been developed in silos. However, the operations of each system depend upon other subsystems within the mega-system, under both extreme and usual circumstances. Lifeline systems are the basic infrastructure that supports all other systems needed for a megacity to function properly. The resiliency of lifeline systems is critical to the sustainability of megacities. Future directions in lifeline systems require improved interactions between the interdependent systems and improved inter-agency coordination. Megacities are extremely vulnerable to risks from natural and man made hazards. Transformative research is needed to better understand how interdependent systems interact and to develop decision support tools that help to understand the performances of complex systems under normal and extreme events. Examples from the Los Angeles megacity region are presented to show the makeup of megacities and mega-systems, and to illustrate their vulnerabilities to extreme events. The simulated performance of water supply and distribution systems in Southern California during a great earthquake scenario are summarized to show how advanced decision support tools may be used for improving the functionality of critical infrastructure systems under normal and extreme circumstances. This study indicates that resilience can be enhanced through multi-system integration and the risks and vulnerabilities to hazards can be overcome through integration of existing infrastructure.