A phylogeny and timescale derived from analyses of multilocus nuclear DNA sequences for Holarctic genera of plethodontid salamanders reveal them to be an old radiation whose common ancestor diverged from sister taxa in the late Jurassic and underwent rapid diversification during the late Cretaceous. A North American origin of plethodontids was followed by a continental-wide diversification, not necessarily centered only in the Appalachian region. The colonization of Eurasia by plethodontids most likely occurred once, by dispersal during the late Cretaceous. Subsequent diversification in Asia led to the origin of Hydromantes and Karsenia, with the former then dispersing both to Europe and back to North America. Salamanders underwent rapid episodes of diversification and dispersal that coincided with major global warming events during the late Cretaceous and again during the Paleocene-Eocene thermal optimum. The major clades of plethodontids were established during these episodes, contemporaneously with similar phenomena in angiosperms, arthropods, birds, and mammals. Periods of global warming may have promoted diversification and both inter- and transcontinental dispersal in northern hemisphere salamanders by making available terrain that shortened dispersal routes and offered new opportunities for adaptive and vicariant evolution.