Bacterial metabolism is comprised of primary metabolites, the intracellular molecules of life that enable growth and proliferation, and secondary metabolites, predominantly extracellular molecules that facilitate a microbe's interaction with its environment. While our knowledge of primary metabolism and its web of interconnected intermediates is quantitative and holistic, significant knowledge gaps remain in our understanding of the secondary metabolomes of bacteria. In this Perspective, I discuss the main challenges involved in obtaining a global, comprehensive picture of bacterial secondary metabolomes, specifically in biosynthetically "gifted" microbes. Recent methodological advances that can meet these challenges will be reviewed. Applications of these methods combined with ongoing innovations will enable a detailed picture of global secondary metabolomes, which will in turn shed light onto the biology, chemistry, and enzymology underlying natural products and simultaneously aid drug discovery.