Butternut is a relatively uncommon hardwood tree native to eastern North America. The species’ abundance has declined over the past 50 years, primarily because of an invasive pathogen (Ophiognomonia clavigignenti-juglandacearum [Oc-j]) and loss of suitable habitat for regeneration. Although genetic diversity of butternut is highest along the southern range edge, genetic diversity rangewide is fairly high, except in small and isolated populations. Although there is little evidence for even moderate resistance in native butternut, hybrids with Japanese walnut, a closely related species, display enough tolerance to infection to persist on the landscape and bear abundant nut crops year after year. Cryostorage of native embryogenic axes has yielded promising initial results as a strategy for gene conservation, but additional action is needed to conserve the remaining native gene pool. We describe a strategy for canker-resistance breeding in butternut using naturally occurring hybrids, hybrids in research orchards, and sources of native trees from as many regions as possible. Forest managers are encouraged to find surviving trees and collect seed for planting in suitable habitat to develop actionable knowledge that will enable the restoration of butternut with enough resistance to be self-sustaining on the landscape.