Paleoproterozoic volcanogenic massive sulfide (VMS) deposits are hosted in greenstone belts that formed during assembly of Earth’s first supercontinent, Nuna, at 2.1 to 1.7 Ga. These deposits account for a significant component of the world’s VMS tonnage and, thus, are an important global exploration target. Among these Paleoproterozoic belts, the 1.92 to 1.80 Ga Trans-Hudson orogen of Canada is the largest and best endowed in Laurentia, with over 29 deposits totaling 320 Mt of Cu-Zn (±Au, Ag, Pb) ore. Study of its deposits, districts, and tectonostratigraphic evolution enables greater understanding of metallogenic and geodynamic processes during the Paleoproterozoic. We briefly overview the Trans-Hudson orogen, its VMS deposits, and their exploration history, and illustrate that various distinct types of volcanogenic massive sulfide deposits form in predictive tectonostratigraphic sequences associated with both pre- and postaccretion volcanism. We present results from a four-year program to investigate the deposits and evolution of the Trans-Hudson orogen, highlighting various approaches at district and belt scales to improve exploration models for other structurally complex and covered Precambrian terranes.