Granitoid batholiths dominated by felsic to intermediate compositions are commonly associated with mafic plutons and enclaves; however, the genetic relationship between the apparently coeval but compositionally dissimilar magmas is unclear. Here, we reviewed the age and lithogeochemical and Nd-Sr isotopic compositions of some classic plutonic rocks emplaced in the Northern Highlands, Grampian and Connemara terranes of the Caledonide orogen of Scotland and Ireland. The Northern Highlands terrane consists mostly of Neoproterozoic metasedimentary rocks of the Moine Supergroup and is located north of the Great Glen fault. The Grampian terrane also consists of Neoproterozoic metasedimentary rocks (Dalradian Supergroup) and is located south of the Great Glen fault in both Scotland and Ireland. Amphibolite-facies metasedimentary rocks in the Connemara terrane are correlated with the Dalradian Supergroup, and the terrane is bounded by splays of the Highland Boundary and Southern Uplands faults. These three terranes were intruded by Silurian–Devonian mafic and felsic to intermediate plutonic rocks that display field evidence for mingling and mixing and have a similar range (between ca. 437 and 370 Ma) in emplacement ages. This range implies they were intruded during and after the late Caledonian Scandian orogenic event that resulted from the mid- to late Silurian collision of amalgamated Avalonia and Baltica with Laurentia and the final closure of the Iapetus Ocean. Our review supports the contention that the Great Glen fault represents a major compositional boundary in the Silurian lithosphere. Felsic to intermediate plutons that occur north of the Great Glen fault are more enriched in light rare earth elements and Ba-Sr-K compared to those to the south. Isotopic compositions of these late Caledonian plutonic rocks on both sides of the Great Glen fault indicate that metasomatism and enrichment of the subcontinental lithospheric mantle beneath the Northern Highlands terrane occurred just prior to emplacement of late Caledonian plutons. Within the same terrane, mafic and felsic to intermediate rocks display similar trace-element and rare earth element concentrations compatible with models implying that fractionation of a mafic magma played an important role in generating the felsic to intermediate magmas. The onset of slab failure magmatism may have been diachronous along the length of the collision zone. If so, slab failure may have propagated laterally, possibly initiating where promontories collided.