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Next‐generation sequencing (NGS) is a powerful, but resource‐intensive technology. Spending money on an experiment that cannot give an answer to the research question at hand is a waste. This chapter addresses several issues in the experimental design of tag‐based expression profiling and chromatin immunoprecipitation (ChIP‐seq) experiments, and provides some practical guidelines for finding the most optimal experimental design. Monitoring of the quality of the different experimental and analytical procedures is also key to the success of NGS experiments. General as well as platform‐ or application‐specific quality control measures and checks are also described.