Natural products (NPs) and their derivatives have historically played a vital role in drug discovery by serving as invaluable sources of therapeutic agents and potential drug leads. Among the established sources of NPs, microorganisms have proven to be the most promising candidates to produce novel scaffolds as well as marketable drugs. They have yielded some of the most economically relevant leads for the pharmaceutical industry, including penicillin G, cephalosporin C, tetracycline, mevastatin and rapamycin. Currently, more than 34,000 bioactive microbial secondary metabolites have been isolated although, it has been estimated that this amount represents less than 10% of the total number of small molecules that these microorganisms are capable to synthesise. Accordingly, novel approaches are needed to replace conventional methodologies that mainly lead to the rediscovery of known compounds and to activate silent (cryptic) gene clusters encoding new natural products. One of these strategies involves the isolation, characterisation, and screening of novel/rare actinomycete taxa sourced from unique and underexplored environments. The chapter thus communicates a new NMR-based methodology used to access into the unique components of the drug-like natural product metabolome of termite gut-associated actinomycetes. This approach was used to accelerate the identification of all the constituents with unique spectral patterns comprising the lead-like enhanced fractions. The effectiveness of the approach resulting in the isolation and identification of six new natural products, namely, actinoglycosidines A (26) and B (27), actinopolymorphol D (28), niveamycin A (32), B (33) and C (34) is discussed.