Mineralization and associated fluid migration events in the ca 1500 km2 North Pennine Orefield (NPO) are known to be associated with tectonic activity, but the age of these tectonic events and origins of the base metal sulphide mineralization remain unresolved. New fieldwork in the Alston Block shows that mineralization post-dates a weakly developed phase of N-S shortening consistent with far-field Variscan basin inversion during the late Carboniferous. New observations of field relationships, coupled with microstructural observations and stress inversion analyses, together with Re-Os sulphide geochronology show that the vein-hosted mineralization (apart from barium minerals) was synchronous with a phase of N-S extension and E-W shortening coeval with emplacement of the Whin Sill (ca 297-294 Ma). Thus the development of the NPO was related to an early Permian regional phase of transtensional deformation, mantle-sourced hydrothermal mineralization and magmatism in northern Britain. Previously proposed Mississippi Valley Type models, or alternatives relating mineralization to the influx of Mesozoic brines can no longer be applied to the development of the NPO in the Alston Block. Our findings also mean that existing models for equivalent base metal sulphide fields worldwide (e.g. Zn-Pb Districts of Silesia, Poland and Tennessee, USA) may need to be reassessed.