Clinically relevant sequencing methodologies continue to expand in number, diversity, complexity, and scale. This evolving and varied landscape requires unique implementations in all aspects of the assay, including the wet bench, bioinformatics, and reporting. Following implementation, the informatics of many of these tests continue to change over time, from software and annotation source updates, guidelines, and knowledgebase changes to changes in underlying information technology (IT) infrastructure. Key principles can be applied when implementing the informatics of a new clinical test which can greatly improve the lab's ability to deal with these updates rapidly and reliably. In this chapter, we discuss a variety of informatics issues which span all NGS applications. In particular, there is the need for implementing a reliable, repeatable, redundant, and version-controlled bioinformatics pipeline and architecture and a discussion of common methodologies to address these needs., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)