The Forest Health Initiative (FHI) was developed and implemented to test the hypothesis that a coordinated effort in biotechnology research could lead to resistant trees capable of restoring a species in a relevant time frame. As a test case, the American chestnut (Castanea dentata) was chosen for study as it is an iconic forest tree species in the eastern United States and southeastern Canada that has been nearly extirpated by chestnut blight which is caused by an introduced fungal pathogen (Cryphonectria parasitica). In addition, the species has attracted research investments over many decades, leading to some promising possibilities for effecting restoration. The FHI, now completing its third year, has integrated genomics-based candidate gene discovery with robust clonal propagation and gene transformation systems capable of producing hundreds of independent events for dozens of genes per year. A promising early leaf assay for blight reaction has been developed that will be instrumental in screening the large amount of material in production through these systems. Regulatory permits for testing some of the earliest transgene events have been obtained as small-scale field testing is beginning. High density genetic maps and various mapping populations are being analyzed to gain additional insights into the specific genes found in quantitative trait loci (QTLs) for resistances to blight and Phytophthora root rot (caused by P. cinnamomi, also known as ink disease). Nearly complete genome sequences of three of the blight resistance QTLs have been determined. These sequences are greatly assisting these analyses, as have comparisons with peach and other completed plant genomes, demonstrating the power of comparative genomics. These results show great promise for meeting the challenge proposed by the FHI hypothesis for American chestnut. In addition, other forest tree species under threat should benefit from similarly designed initiatives.