Extreme environments such as hyperarid, hypersaline, hyperthermal environments, and the deep sea harbor diverse microbial communities, which are specially adapted to extreme conditions and are known as extremophiles. These extremophilic organisms have developed unique survival strategies, making them ideal models for studying microbial diversity, evolution, and adaptation to adversity. They also play critical roles in biogeochemical cycles. Additionally, extremophiles often produce novel bioactive compounds in response to corresponding challenging environments. Recent advances in technologies, including genomic sequencing and untargeted metabolomic analysis, have significantly enhanced our understanding of microbial diversity, ecology, evolution, and the genetic and physiological characteristics in extremophiles. The integration of advanced multi-omics technologies into culture-dependent research has notably improved the efficiency, providing valuable insights into the physiological functions and biosynthetic capacities of extremophiles. The vast untapped microbial resources in extreme environments present substantial opportunities for discovering novel natural products and advancing our knowledge of microbial ecology and evolution. This review highlights the current research status on extremophilic microbiomes, focusing on microbial diversity, ecological roles, isolation and cultivation strategies, and the exploration of their biosynthetic potential. Moreover, we emphasize the importance and potential of discovering more strain resources and metabolites, which would be boosted greatly by harnessing the power of multi-omics data.