Agaricus bisporus is a globally cultivated crop produced and consumed worldwide. This monoculture system and the advancement of consolidated growth of pre-colonised A. bisporus compost has coincided with the outbreak of a novel commercial disease, mushroom virus X (MVX). MVX constitutes a virome of 18 distinct single-stranded RNA viruses, of which select members cause detrimental disease phenotypes in infected mushrooms of A. bisporus. Scant focus has been placed on the molecular responses from the host during infection. The work presented herein provides novel genomic, transcriptomic, proteomic and cellular resources to help address the gaps in knowledge concerning MVX and A. bisporus. The first whole genome sequencing and analysis of a wild A. bisporus var. bisporus was provided as a new resource for A. bisporus breeding research, revealing to be most closely related to the commercial white variety with a large accessory genome compared to other A. bisporus genomes. Dual-culture assays revealed the potential for MVX to transmit through hyphal fusion (anastomosis) into a variety of strains, whereas diagnostics of fruit bodies revealed different susceptibilities in certain strains with wild germ plasms. Mechanisms of anastomosis were revealed in varietal interactions and showed evidence of hyphae remodelling in compatible strains, metabolic starvation responses in competing interactions and antagonistic oxidative stresses in vegetative incompatible interactions. Molecular responses revealed increased regulation in gene expression, vesicle transport and ER-stress responses in virus infected fruit bodies, with less susceptible strains revealing increases of antiviral protein responses, general stress responses, lipid metabolism. The intracellular localisation of two of these viruses related to different symptomologies in infected fruit bodies revealed distinct patterns of virus distribution and characteristics related to persistent nature of infection. This work has provided novel insights into the molecular aspects of A. bisporus and MVX and the challenges they pose for the mushroom industry.