South Sister is southernmost and highest of the Three Sisters, three geologically dissimilar stratovolcanoes that together form a spectacular 20 km reach along the Cascade crest in Oregon. North Sister is a monotonously mafic edifice as old as middle Pleistocene, Middle Sister a basalt-andesite-dacite cone built between 48 and 14 ka, and South Sister is a basalt-free edifice that alternated rhyolitic and intermediate modes from 50 ka to 2 ka (largely contemporaneous with Middle Sister). Detailed mapping, 330 chemical analyses, and 42 radioisotopic ages show that the oldest exposed South Sister lavas were initially rhyolitic ~ 50 ka. By ~ 37 ka, rhyolitic lava flows and domes (72-74% SiO 2) began alternating with radially emplaced dacite (63-68% SiO 2) and andesite (59-63% SiO 2) lava flows. Construction of a broad cone of silicic andesite-dacite (61-64% SiO 2) culminated ~ 30 ka in a dominantly explosive sequence that began with crater-forming andesitic eruptions that left fragmental deposits at least 200 m thick. This was followed at ~ 27 ka by growth of a steeply dipping summit cone of agglutinate-dominated andesite (56-60.5% SiO 2) and formation of a summit crater ~ 800 m wide. This crater was soon filled and overtopped by a thick dacite lava flow and then by > 150 m of dacitic pyroclastic ejecta. Small-volume dacite lavas (63-67% SiO 2) locally cap the pyroclastic pile. A final sheet of mafic agglutinate (54-56% SiO 2) - the most mafic product of South Sister - erupted from and drapes the small (300-m-wide) present-day summit crater, ending a summit-building sequence that lasted until ~ 22 ka. A 20 kyr-long-hiatus was broken by rhyolite eruptions that produced (1) the Rock Mesa coulee, tephra, and satellite domelets (73.5% SiO 2) and (2) the Devils Chain of ~ 20 domes and short coulees (72.3-72.8% SiO 2) from N-S vent alignments on South Sister's flanks. The compositional reversal from mafic summit agglutinate to recent rhyolites epitomizes the frequently changing compositional modes of the South Sister locus throughout its lifetime. South Sister is part of a reach of the Cascades unusually active in the last 50 kyr, characterized by high vent density, N-S vent alignments, and numerous eruptive units of true rhyolite (≥ 72% SiO 2) that distinguishes it from much of the Quaternary Cascade arc; these are eruptive expressions of the complex confluence of arc and intraplate magmatic-tectonic regimes.