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A scale-out system is a collection of interconnected, modular, low-cost computers that work as a single entity to cooperatively provide applications, systems resources, and data to users. The dominant programming model for such systems consists of message passing at the systems level and multithreading at the element level. Scale-out computers have traditionally been developed and deployed to provide levels of performance (throughput and parallel processing) beyond what was achievable by large shared-memory computers that utilized the fastest processors and the most expensive memory systems. Today, exploiting scale-out at all levels in systems is becoming imperative in order to overcome a fundamental discontinuity in the development of microprocessor technology caused by power dissipation. The pervasive use of greater levels of scale-out, on the other hand, creates its own challenges in architecture, programming, systems management, and reliability. This position paper identifies some of the important research problems that must be addressed in order to deal with the technology disruption and fully realize the opportunity offered by scale-out. Our examples are based on parallelism, but the challenges we identify apply to scale-out more generally.