40Ar/39Ar, apatite fission-track, and apatite (U-Th)/He thermochronological techniques were used to determine the Neogene exhumation history of the topographically asymmetric eastern Alaska Range. Exhumation cooling ages range from ~33 Ma to ~18 Ma for 40Ar/39Ar biotite, ~18 Ma to ~6 Ma for K-feldspar minimum closure ages, and ~15 Ma to ~1 Ma for apatite fission-track ages, and apatite (U-Th)/He cooling ages range from ~4 Ma to ~1 Ma. There has been at least ~11 km of exhumation adjacent to the north side of Denali fault during the Neogene inferred from biotite 40Ar/39Ar thermochronology. Variations in exhumation history along and across the strike of the fault are influenced by both far-field effects and local structural irregularities. We infer deformation and rapid exhumation have been occurring in the eastern Alaska Range since at least ~22 Ma most likely related to the continued collision of the Yakutat microplate with the North American plate. The Nenana Mountain region is the late Pleistocene to Holocene (~past 1 Ma) primary locus of tectonically driven exhumation in the eastern Alaska Range, possibly related to variations in fault geometry. During the Pliocene, a marked increase in climatic instability and related global cooling is temporally correlated with an increase in exhumation rates in the eastern Alaska Range north of the Denali fault system.