Regional-scale magnetite-destructive structures transecting the allochthonous to parautochthonous Intermontane terranes of western Yukon are characterized by northwest-trending and steeply north-east dipping fault systems, whereas eastern Alaska is dominated by a series of northeast-trending and sub-vertical faults. At a local scale, geological, structural and geophysical data support the role of these structures in focusing of orogenic style and magmatic-related mineralization under contractional and strike-slip tectonics, respectively. Orogenic gold mineralization in the Klondike and White Gold districts is closely linked to contractional deformation and to cooling of upper plate rocks in the Middle to Late Jurassic, following accretion and amalgamation of the Intermontane terranes to the Laurentian margin. Orogenic gold mineralization associated with this event formed in a variety of structural settings, including orogen-parallel thrust surfaces, breccias and veins in orogen-perpendicular to oblique transfer faults, and dilational veins hosted in fold-related shear and tensional fractures. This phase of Jurassic northeast-southwest directed contraction was followed by northwest-southeast extension by Early to mid-Cretaceous time and to transtension in the Late Cretaceous. In the Yukon’s Dawson Range, mid-Cretaceous epizonal orogenic gold mineralization (Coffee Gold Au system) and early Late Cretaceous porphyry Cu-Au(-Ag-Mo) systems (e.g., Casino, Nucleus, Revenue, Cash) are structurally related to the northwest-trending, dextral strike-slip Big Creek fault, which represents a branch of the Teslin-Thibert-Kutcho fault system of southern Yukon and northern British Columbia. By the latest Cretaceous, defomation is dominated by northeast-trending sinistral strike-slip magnetite-destructive faults (e.g., Pb-Ag veins of the Sixtymile and Fortymile districts of far western Yukon and eastern Alaska). We interpret fault bends, fault relay zones and fault tips, as well as lower-order structures, to favour the formation of mid- to Late Cretaceous magmatic-related mineralization.