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The migration of semiconductor processes to single-wafer vacuum cluster tools has rendered configuration an important decision variable in fab operation and heightened the impact of reliability on fab performance. We address these closely linked issues by deriving the optimal configuration and operation of systems of cluster tools in the presence of scheduled maintenance. The two extremes in the spectrum of possible configurations are the serial configuration, in which the modules in a tool are all different, each representing a step in a process sequence, and the parallel configuration, in which each tool is assigned only one process step. We predict that the latter can offer higher throughputs. However, this advantage may be slight when equipment downtime is relatively schedulable and infrequent, in which the case the serial configuration may be preferable because of its superior cycle times. We also derive optimal lot sizing and release policies for systems of cluster tools. We conclude that fabs will gradually migrate from parallel configurations to serial as cluster tools become more reliable and cycle time becomes more important.