There is a worldwide surge in fungal infections due to increased longevity in the human population, prevalence of individuals with compromised immune systems, and widespread use of antibiotics fueling a surge in drug-resistant strains. To design novel strategies to overcome resistance to antifungals, we need to address the gap in knowledge of the molecular mechanisms that enable pathogenic fungi to overcome the metabolic stress of antifungal treatments. Our long-term research goal is to identify key metabolic processes that enable infectious fungi to survive under stress conditions as potential targets for therapeutic antifungals. Our approach is to identify key signaling molecules controlling metabolic mechanisms in the budding yeast Saccharomyces cerevisae that are evolutionarily conserved in pathogenic fungi, and promote fungal survival under conditions of physiological stress. Normal or pathogenic stress conditions that can compromise cellular integrity such as: cell wall damage by chemical agents (antifungal agents, antibiotics, etc.), heat shock, oxidizing chemicals such as hydrogen peroxide, are detected by stress mechanosensor proteins in the plasma membrane of S. cerevisae. These mechanosensor proteins physically interact with specific signaling proteins that transduce stress signals from the fungal cell wall to the cytosol where the signaling machinery initiates the survival response. Our current research is therefore focused on the identification and functional characterization of key signaling proteins that interact with these mechanosensor proteins to confer resistance to antifungal drugs, oxidizing chemicals, and heat stress.