The discovery of new chemical entities from natural sources has been historically driven by the biological activity observed in crude extracts or by the significant abundance of secondary metabolites, through a laborious workflow, frequently culminating on the re-isolation of known compounds. This high rate of rediscovery was one of the main contributing factors leading to the decreased interest in natural products from pharmaceutical companies and academic research groups until very recently. Largely driven by the technological advances in analytical instrumentation, mainly mass spectrometry (MS) and nuclear magnetic resonance (NMR), a renaissance on natural products research and associated drug discovery programs is being witnessed. The development of hybrid platforms combining the strengths of MS and NMR enables a faster and more accurate identification of known metabolites, allowing the prioritization of new natural products, not only with new chemical scaffolds but also frequently exhibiting relevant biological effects that may ultimately provide new lead drugs. Furthermore, the synergism resulting from the combination of both techniques allows almost unlimited access to the chemical space available formed by new natural sources.