Fungi, including yeasts, have played a central role in the development of knowledge about cell physiology and molecular biology as experimental eukaryotic models. However, much of this knowledge has been generated using classical organisms such as Saccharomyces cerevisiae, which display inherent limitations, as many cellular processes operate under extreme conditions, including high salinity, extreme pH, oxidative stress, exposure to toxic compounds, and temperature fluctuations. In this context, extremophilic and extremotolerant yeasts have emerged as complementary systems with strong potential for basic research and biotechnological applications. This review integrates recent advances in the taxonomic diversity, ecology, physiology, molecular mechanisms, and omics-based analyses of extremophilic yeasts, with a particular focus on how these organisms achieve stress integration through coordinated regulation of signaling pathways, metabolism, and organelle function. We discuss representative applications in environmental toxicology, bioremediation, and industrial bioprocesses, as well as their relevance in the context of climate change and space biotechnology. Finally, we outline key conceptual and methodological challenges and propose future perspectives that position extremophilic yeasts as next-generation eukaryotic models for investigating adaptation as a systems-level, constitutive cellular state under complex and dynamic stress conditions.