Aspergillus fumigatus represents an ever-present threat for vulnerable individuals as fungal conidia are ubiquitous and are inhaled daily. Infection occurs when optimal conditions are present resulting in a range of disease states, primarily in the context of preexisting lung damage and immunosuppression. Despite the threat this species imposes it appears to be an accidental pathogen as its primary niche is as a saprophyte in decaying plant matter. Survival in the soil has shaped A. fumigatus traits that facilitate survival in human host. This existence also equipped A. fumigatus with an array of effectors that have cross-reactivity through targeting of conserved mechanisms which can be repurposed to survive in the human body. The human lung is a terminal host for fungal development and dissemination and as such the fungus can only aim to survive but not disseminate. The lung represents a hostile environment consisting of challenges from the innate immune response, nutrient limitation and competition with microorganisms competing for the same limited resources. The rates of A. fumigatus infections are increasing globally, compounded by climate change and the rise in drug resistant strain. Despite the growing burden of disease, the mechanisms governing host adaptation and persistence remain poorly elucidated. To examine the host adaptation processes occurring in the lung, phenotypic and proteomic analysis of A. fumigatus growth in response to isolated aspects of this environment was performed. Examination of A. fumigatus development using Galleria mellonella as an innate immune system analogue, patterns regarding fungal metabolic preferences and virulence factor production have been further characterised. Prolonged subculture of A. fumigatus within an agar system containing components of the immune response and the nutritional profile of G. mellonella identified reduced virulence and increased tolerance to oxidative stress and antifungal agents. These changes were governed by minor alteration to the fungal proteome, suggesting the requirements for survival as an environmental saprobe to persistence in a human host may not be a difficult transition. Examination of released fungal proteins in vivo in G. mellonella demonstrated an initial preference for carbon metabolism and an emphasis on amino acid metabolism in later stages of infection which may fuel the production of fungal secondary metabolites. Similar trends were observed in the ex-vivo pig lung (EVPL) model, an analogue of host lung tissue, where A. fumigatus induced immune activation and fibrosis within the tissue. Similar metabolic patterns and secondary metabolites were detected during colonisation in this model. Characterisation of fungal growth in response to bacterial lung pathogens identified secreted product of Klebsiella pneumoniae could induce secondary metabolite production including gliotoxin and inhibited fungal growth. Physical interaction with P. aeruginosa also demonstrated inhibited fungal development in the EVPL model. These studies provide key insight into the initial interaction of the fungus to its host and highlights key metabolic and fungal developmental factors integral to successful colonisation. These insights can be utilised in the development of next generation, more effective and specific antifungal agents to treat this deadly disease.