Streptomyces are a group of Gram-positive, filamentous bacteria that have the ability to produce a great diversity of structurally unique secondary metabolites with a potential for biological activity. There is evidence of newly discovered Streptomyces species with a broad range of biosynthetic capabilities from frigid climates and geothermal springs while working in harsh conditions. These Streptomyces strains that thrive in harsh environments are categorised as extremophiles because they have evolved specialised metabolic pathways and the capacity to withstand high salinities, high temperatures, or high-pressure situations. The advent of next-generation sequencing technologies, modifications to metabolite screening protocols, and other precise techniques have made it possible to identify a number of cryptic biosynthetic gene clusters, most of which are unknown under typical laboratory conditions. In this chapter, we demonstrate how strains of Streptomyces from extreme environments yield novel bioactive leads. We also identified the challenges of studying these organisms and listed solutions that are environmentally sensitive and innovative approaches to biosampling and cultivation strategies, which will indicate the metabolic potential of microorganisms in extreme environments. The ultimate goal is the discovery of new next-generation therapeutics and sustainable food production methods. Genomics, metabolomics, and synthetic biology are reaching a turning point in their efforts to activate novel metabolic pathways from microorganism biospecimens.