Over 70 major (>1 million metric tons) strata-bound and stratiform sulfide deposits of late Proterozoic and early Paleozoic age in the fragmented Appalachian-Caledonian orogen are correlated on the basis of their paleotectonic setting. The latter is defined in terms of two parameters, the plate tectonic paleosetting and the paleogeographic location relative to various cratonic margins. Attention is focused on geochemical data from mafic volcanic and high-level intrusive rocks associated with massive sulfide deposits, as well as on structural settings and regional tectonostratigraphic correlations. Host-rock data for over 20 key deposits or groups of deposits are discussed.Massive sulfides formed in intraplate (ensialic) as well as ocean-floor and convergent plate boundary settings are recognized in the orogen. The intraplate (ensialic) setting involves environments marginal to the Laurentian and Baltoscandian cratons; it includes both sedimentary and volcanic host-rock sequences and is interpreted as an incipient divergent plate boundary. The ocean-floor setting includes massive sulfides in ophiolites formed either at a major ocean spreading axis or within back- or interarc basins, as well as deposits hosted by sequences of mafic volcanics, graphitic phyllite, and chert possibly formed in an off-axis (intraplate) situation; deposits in this setting are restricted to the northern Appalachians and the Norwegian Caledonides. The convergent plate boundary setting includes massive sulfides hosted by subduction-related volcanics, and by postarc and post-early collision volcano-sedimentary sequences. Both ensimatic and ensialic subarc crustal environments are represented, the latter recognized outboard (northwest) of the Avalonian platform in the Appalachians and its equivalent in the United Kingdom-Ireland Caledonides. The majority of massive sulfide deposits in the orogen formed within a convergent plate boundary setting.Assessment of the host-rock data in connection with the correlation theme has revealed: (1) the presence of both regional and sulfide-localized alterations in volcanic host rocks and the occurrence of sulfide-localized alteration in several of the sediment-hosted deposits; (2) evidence for an extensional tectonic regime either during or immediately after deposition of many of the massive sulfide deposits, including some of those formed in a convergent plate boundary setting (rifted-arc, postarc, and post-early collision sequences); (3) the likelihood that massive sulfides were deposited during a single cycle of ocean basin opening and closure, although possible reservations to this model are raised by volcanic-hosted deposits in the southern Appalachians; and (4) possible target areas for future mineral exploration.