Because of the importance of microbes as model organisms, biotechnology tools, and contributors to mammalian and ecosystem metabolism, there has been longstanding interest in measuring their metabolite levels. Current metabolomic methods, involving mass spectrometry-based measurement of cell extracts, enable routine quantitation of most central metabolites. Metabolomics alone, however, is inadequate to understand cellular metabolic activity: Flux measurement and proteomic, genetic, and biochemical approaches with a metabolomics bent are all needed. Here we highlight examples where these integrated methods have contributed to discovery of metabolic pathways, regulatory interactions, and homeostasis mechanisms. We also indicate enduring challenges concerning unstable and low abundance compounds, subcellular compartmentalization, and quantitative amalgamation of different data types.