Architecture simulation tools are extremely useful not only to predict the performance of future system designs, but also to analyze and improve the performance of software running on well know architectures. However, since power and complexity issues stopped the progress of single-thread performance, simulation speed no longer scales with technology: systems get larger and faster, but simulators do not get any faster. Detailed simulation of full-scale applications running on large clusters with hundreds or thousands of processors is not feasible. In this paper we present a methodology that allows detailed simulation of large-scale MPI applications running on systems with thousands of processors with low resource cost. Our methodology allows detailed processor simulation, from the memory and cache hierarchy down to the functional units and the pipeline structure. This feature enables software performance analysis beyond what performance counters would allow. In addition, it enables performance prediction targeting non-existent architectures and systems, that is, systems for which no performance data can be used as a reference. For example, detailed analysis of the weather forecasting application WRF reveals that it is highly optimized for cache locality, and is strongly compute bound, with faster functional units having the greatest impact on its performance. Also, analysis of next-generation CMP clusters show that performance may start to decline beyond 8 processors per chip due to shared resource contention, regardless of the benefits of through-memory communication.