Emerging fungal pathogens such as Candida auris, Lomentospora prolificans, and Scedosporium spp. present urgent clinical challenges due to their intrinsic antifungal resistance and ability to cause invasive disease in immunocompromised patients. The molecular basis of their interactions with host epithelial cells remains poorly defined. This dissertation develops a multi-omics discovery strategy that integrates affinity pulldown assays, quantitative proteomics, phosphoproteomics, and transcriptomics to identify host receptors mediating fungal adhesion. Three receptors—integrin ß4 (ITGß4), epidermal growth factor receptor (EGFR), and hepatocyte growth factor receptor (c-MET)—were prioritized. Functional assays demonstrated that ITGß4 is a conserved adhesion receptor for multiple fungal species, with chitin identified as a candidate ligand. In parallel, phosphoproteomic profiling revealed that L. prolificans dynamically modulates host signaling through EGFR and c-MET phosphorylation. These findings define ITGß4, EGFR, and c-MET as clinically relevant host receptors, providing novel insight into epithelial pathogenesis and establishing potential targets for host-directed antifungal interventions.