ABSTRACT Invasive aspergillosis (IA) caused by Aspergillus fumigatus is characterized by uncontrolled filamentous hyphal growth deep into host tissues and is a fatal disease of immunocompromised patients with mortality rates as high as 90%. This high mortality rate indicates the critical need for improved antifungal therapeutic strategies. We have uncovered a bidirectional lipid signaling system between the fungus and host that mediates invasive hyphal growth and phagocyte activation. Based on strong preliminary data, this communication system consists of structurally similar fungal and host ligands (e.g. oxylipins) that are recognized by two fungal and one host G protein coupled receptor (GPCR). The fungal and host oxylipins work in opposition to regulate fungal growth and neutrophil chemotaxis. We hypothesize that fungal and host oxylipins are cross-Kingdom molecular analogs that signal through specific GPCR cascades, inducing penetrating hyphal growth and manipulating host defense responses to drive IA progression. Our data not only provide new insight into how eukaryotic pathogens and their hosts communicate with one another directly during disease but also provide a new foundation for experimental approaches to decipher, manipulate, and control this communication system in favor of the host. Accordingly, we will (1) Identify the oxylipins and their transcriptional cascades that regulate invasive branching growth and (2) Characterize the receptors by which fungus and host recognize each other’s oxylipins and the consequences of this recognition. GPCR are particularly propitious targets for therapeutic design (40% of current pharmaceuticals target GPCR). Thus, upon completion of this work, we anticipate that we will have delineated a new fungal-host ligand-receptor communication language amenable to therapeutic intervention to inhibit filamentous invasive growth during human disease.