The Central Dogma describes how genes are transcribed into mRNA that is translated into proteins, but it says nothing about when or how much. This is the realm of epigenomes and epitranscriptomes – nucleic acid modifications scheduling gene expression. We develop new tools for studying DNA and RNA modifications in health and disease. One platform coordinates genomics, DNA-seq, and mass spectrometry to discover new DNA modifications, such as phosphorothioates in the microbiome. For epitranscriptomes, we applied systems-level analytics to discover a cell response mechanism involving stress-induced reprogramming of 50+ tRNA modifications causing selective translation of codon-biased stress-specific mRNAs. Applying these tools to pathogenic microbes has revealed new mechanisms of adaptive response and potential therapeutic targets.