Infrastructures provide the foundation for national economic vitality, security and every day comforts. The systems, processes, facilities and experts that form these infrastructures are sophisticated, complex and highly interdependent. Over time, these physical, human and cyber components have evolved toward economical and efficient systems that are robust against random failures and natural events. This evolution creates greater interconnectedness and complexity. Modeling is an essential process for anticipating and understanding how these complex, interdependent systems will respond to disruptions and changing conditions. Natural disasters, malevolent attacks, changes in regulations or market policy all have the potential to disrupt the flow of infrastructure goods and services. No single model or modeling approach is sufficient for answering the breadth of near-term and long-term questions being asked relative to critical infrastructure protection at a local to international level. This article presents the results of six years of model development at the National Infrastructure Simulation and Analysis Center (NISAC), USA; including the types of models developed, their utility in answering critical infrastructure protection questions and general insights regarding infrastructure behaviors and propagating effects of disruptions.