Recent years have seen tremendous progress in next generation sequencing technologies, allowing genomic sequencing in a highly cost-effective manner. However, sample preparation for these sequencers remains a bottleneck as the human genome is too complex to be routinely resequenced. We present here an in-depth study of HybSelect, a method that can specifically enrich a large number of genes or regions of interest from any chromosomal DNA. The study used Escherichia coli K12 MG1655 as a model organism to test parameters such as method fidelity, capacity or reproducibility as a proof-of-principle.