<p>Eastern black walnut (<i>Juglans nigra</i> L.) ranks among the most highly valued timber species in the central hardwood forest and across the world. This valuable tree fills a critical role in native ecosystems as a mast bearing pioneer on mesic sites. Along with other <i>Juglans</i> spp. (Juglandaceae), <i>J. nigra</i> is threatened by thousand cankers disease (TCD), an insect-vectored disease first described in 2009. TCD is caused by the bark beetle <i>Pityophthorus juglandis</i> Blackman (Corthylini) and the phytopathogenic fungus <i>Geosmithia morbida</i> Kol. Free. Ut. & Tiss. (Bionectriaceae). Together, the <i>P. juglandis</i>-<i>G. morbida</i> complex has expanded from its historical range in southwest North America throughout the western United States (U.S.) and Europe. This range expansion has led to widespread mortality among naïve hosts <i>J. nigra</i> and <i>J. regia</i> planted outside their native distributions.</p> <p> The severity of TCD was previously observed to be highest in urban and plantation environments and outside of the host native range. Therefore, the objective of this work was to provide information on biotic and abiotic environmental factors that influence the severity and impact of TCD across the native and non-native range of <i>J. nigra</i> and across different climatic and management regimes. This knowledge would enable a better assessment of the risk posed by TCD and a basis for developing management activities that impart resilience to natural systems. Through a series of greenhouse-, laboratory- and field-based experiments, environmental factors that affect the pathogenicity and/or survival of <i>G. morbida</i> in <i>J. nigra</i> were identified, with a focus on the microbiome, climate, and opportunistic pathogens. A number of potentially important interactions among host, vector, pathogen and the rest of the holobiont of TCD were characterized. The <i>holobiont</i> is defined as the whole multitrophic community of organisms—including <i>J. nigra</i>, microinvertebrates, fungi and bacteria—that interact with one another and with the host.</p> <p>Our findings indicate that interactions among host, vector, pathogen, secondary pathogens, novel microbial communities, and novel abiotic environments modulate the severity of TCD in native, non-native, and managed and unmanaged contexts. Prevailing climatic conditions favor reproduction and spread of <i>G. morbida</i> in the western United States due to the effect of wood moisture content on fungal competition. The microbiome of soils, roots, and stems of trees and seedlings grown outside the host native range harbor distinct, lower-diversity communities of bacteria and fungi compared to the native range, including different communities of beneficial or pathogenic functional groups of fungi. The pathogen <i>G. morbida</i> was also associated with a distinct community of microbes in stems compared to <i>G. morbida</i>-negative trees. The soil microbiome from intensively-managed plantations facilitated positive feedback between <i>G. morbida</i> and a disease-promomting endophytic <i>Fusarium solani</i> species complex sp. in roots of <i>J. nigra</i> seedlings. Finally, the nematode species <i>Bursaphelenchus juglandis</i> associated with <i>P. juglandis</i> synergizes with <i>G. morbida</i> to cause foliar symptoms in seedlings in a shadehouse; conversely, experiments and observations indicated that the nematode species <i>Panagrolaimus</i> sp. and cf. <i>Ektaphelenchus</i> sp. could suppress WTB populations and/or TCD outbreaks.</p> <p>In conclusion, the composition, function, and interactions within the <i>P. juglandis</i> and <i>J. nigra</i> holobiont play important roles in the TCD pathosystem. Managers and conservationists should be aware that novel associations outside the host native range, or in monocultures, intensive nursery production, and urban and low-humidity environments may favor progression of the disease through the effects of associated phytobiomes, nematodes, and climatic conditions on disease etiology. Trees in higher diversity, less intensively managed growing environments within their native range may be more resilient to disease. Moreover, expatriated, susceptible host species (<i>i.e.</i>, <i>J. nigra</i>) growing in environments that are favorable to novel pests or pest complexes (<i>i.e.</i>, the western U.S.) may provide connectivity between emergent forest health threats (<i>i.e.</i>, TCD) and native host populations (<i>i.e.</i>, <i>J. nigra</i> in its native range).</p>