An organisms’ metabolism is fundamental to its survival. Metabolism, which is principally an organisms’ collection of biochemical transformations, inherently requires the development of reactive metabolites for transformations to occur. Metabolites such as adenylated acids and coenzyme A thioesters, biochemical moieties found in all living systems, only persist with half-lives on the order of minutes to days. Standard metabolomic methods lack the ability to detect reactive metabolites which ultimately remain invisible to typical analytical techniques. Current specialized techniques for detecting reactive metabolites usually require laborious, technically challenging protocols, and ubiquitously lack the capacity to enable untargeted applications. Modern advances in high-resolution mass spectrometry can detect hundreds of thousands of features in a single sample, adding to the complexity of deconvoluting signatures of the reactive metabolome. This dissertation explores the development of tools to reveal metabolites that were either difficult or impossible to previously detect. Coupling high-resolution tandem mass spectrometry to untargeted metabolomic tools reveals a multitude of metabolites, many of which reveal new biology, biosyntheses, and biochemistries. Although the model organism Caenorhabditis elegans is predominantly utilized in this body of work, the tools developed in this dissertation can be applied to virtual any living system.