Polyextremophilic microbiomes—that is, assemblages of microbes able to live within multiple extreme environments—stand out as a frontier in both microbial ecology and sustainable agriculture. This chapter presents an overview of polyextremophilic microorganisms from their defining features to the diverse extreme environments from which they evolve. We discuss the molecular and physiological responses allowing these microbes to thrive under severe stress conditions, including high salt concentration, acidity, temperature variations, desiccation, or nutrient deprivation. Functions of polyextremophilic microbiomes in the agricultural soil are considered with a focus on their involvement in organic matter degradation and vital nutrients biogeochemical cycles. The chapter further explores the increasing biotechnological applications of these microbes in agriculture as microbial inoculants, biofertilizers, and biopesticides on stress-tolerant crops and for the remediation of contaminated soils. We have also emphasized polyextremophiles as potential contributors to climate change resilience in agroecosystems, focusing on soil stabilization and plant resistance to environmental stress. Methodological approaches for studying, cultivating, and applying polyextremophilic microbiomes are presented alongside current limitations and challenges. Overall, this chapter highlights the ecological importance and applied potential of polyextremophiles and suggests ways in which their potential as tool organisms for sustainable agriculture can be exploited in the future.