Covering: up to the end of 2013 The in-depth analysis of secondary metabolomes of many microbes offers tremendous opportunities for the discovery of novel natural products which often exhibit promising biological activities. However, over the last years the increasing availability of whole-genome information has led to raised expectations, as bioinformatic analysis revealed that traditional strategies to discover novel secondary metabolites apparently have so far only scratched the surface of the real microbial “secondary metabolome landscape”. Metabolomics-based approaches using modern mass spectrometry techniques can help to bridge the gap between genome-encoded potential for the production of secondary metabolites and the usually contradictory low numbers of compounds known from a specific producer. In this article recent studies are highlighted in which metabolomics-driven analysis played a crucial role for the discovery of novel secondary metabolites from microbial sources. We also exemplify how the implementation of metabolomics techniques facilitates the structural characterization of novel metabolites and contributes to the in-depth investigation of underlying biosynthetic pathways. Furthermore, the constantly increasing role of secondary metabolomics for the identification of novel natural products in a drug discovery context is discussed.