Natural products originating from microorganisms have been an important source of many successful lead molecules in the drug discovery and development process. The technological advances in analytical instrumentation and the development of various omics methodologies have provided new opportunities to accelerate the discoveries of new lead structures of microbial origin. Metabolomics is a rapidly emerging omics-based platform for the identification of diverse microbial metabolites on a large scale. The chapter emphasizes the importance of microbial metabolomics in identifying bioactive compounds and provides a general overview of the standard workflow of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy-based metabolomics to identify large numbers of metabolites from cells. In addition, the chapter focuses on the synergistic use of multi-omics approaches—genomics, transcriptomics, proteomics, and metabolomics—in the discovery of novel drug molecules from microbial sources. Special attention is given to how integrative omics techniques improve the identification and characterization of microbial natural products, including how genomics and metabolomics or transcriptomics and metabolomics work together to guide the discovery process. The synergistic use of multiple omics techniques in identifying the microbial targets to treat infectious diseases is also highlighted.