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An "in house" taxonomic approach to drug discovery led to the isolation of diverse actinobacteria from hyper-arid, extreme hyper-arid and very high altitude Atacama Desert soils. A high proportion of the isolates were assigned to novel taxa, with many showing activity in standard antimicrobial plug assays. The application of more advanced taxonomic and screening strategies showed that strains classified as novel species of Lentzea and Streptomyces synthesised new specialised metabolites thereby underpinning the premise that the extreme abiotic conditions in the Atacama Desert favour the development of a unique actinobacterial diversity which is the basis of novel chemistry. Complementary metagenomic analyses showed that the soils encompassed an astonishing degree of actinobacterial ’dark matter’, while rank-abundance analyses showed them to be highly diverse habitats mainly composed of rare taxa that have not been recovered using culture-dependent methods. The implications of these pioneering studies on future bioprospecting campaigns are discussed.