Ganoderma species are well-documented pathogens of a wide range of woody hosts. Recently, Ganoderma adspersum has been observed to be associated with wood decay and tree failure in California almond orchards. The purpose of this study was to investigate the pathogenicity, infectivity, and transmission of G. adspersum associated with increasing tree failure in California’s Central Valley. To date, no studies have investigated the pathogenicity of Ganoderma species in agricultural and native trees in California. Pathogenicity tests were conducted to determine the pathogenicity of G. adspersum and G. brownii (a native Ganoderma species in California) on almond, walnut, pistachio, and oak trees. Inoculations were made by coring into the sapwood of the saplings’ basal stem and pipetting Ganoderma spore solutions into the wounds. In two greenhouse trials, 10 months post-inoculation, trees had no visual, external symptoms of disease, although there were differences in the extent of internal wood decay and xylem discoloration. Ganoderma adspersum caused extensive discoloration and was reisolated from Nemaguard and Viking rootstock cultivars. The data suggest that these Ganoderma species were pathogens capable of infecting healthy sapwood of almond. Disease surveys in almond orchards revealed substantial tree losses associated with G. adspersum. In one case, tree losses resulted in early removal of a 19-20-year-old orchard. A two-year long spore survey in almond orchards revealed that the majority of spores were trapped during increased temperatures and almond harvest from August to September. These findings suggest the need to assess management practices to reduce dust production and G. adspersum spore transmission in California orchards. In field conditions, G. adspersum was often associated with bacterial colonization of Agrobacterium tumefaciens, causal agent of crown gall. The high co-incidence of the fungal and bacterial pathogens suggests potential synergystic effects in pathogenesis. However, co-inoculation assays have shown that the pathogens do not significantly interact with each other nor promote increased initial disease development. The rise of multi-pathogen diseases in almonds likely results from the rapid adoption of high-density planting, mechanized harvesting, and increased inputs of irrigation and fertilization, which create an environment that facilitates the infection and establishment of multiple pathogens.