Climate change is unleashing novel biotic antagonistic interactions for forest trees that may jeopardize populations’ persistence. Therefore, this review article envisions highlighting major opportunities from ecological evolutionary genomics to assist the identification, conservation, and breeding of biotic resistance in forest tree species. Specifically, we first discuss how assessing the genomic architecture of biotic stress resistance enables us to recognize a more polygenic nature for a trait typically regarded Mendelian, an expectation from the Fisherian runaway pathogen–host concerted arms-race evolutionary model. Secondly, we outline innovative pipelines to capture and harness natural tree pre-adaptations to biotic stresses by merging tools from the ecology, phylo-geography, and omnigenetics fields within a predictive breeding platform. Promoting integrative ecological genomic studies promises a better understanding of antagonistic co-evolutionary interactions, as well as more efficient breeding utilization of resistant phenotypes.