Late Holocene volcanism at Medicine Lake volcano in the southern Cascades arc exhibited widespread and compositionally diverse magmatism ranging from basalt to rhyolite. Nine well-characterized eruptions have taken place at this very large rear-arc volcano since 5,200 years ago, an eruptive frequency greater than nearly all other Cascade volcanoes. The lavas are widely distributed, scattered over an area of ~300 km² across the >2,000-km² volcano. The eruptions are radiocarbon dated and the ages are also constrained by paleomagnetic data that provide strong evidence that the volcanic activity occurred in three distinct episodes at ~1 ka, ~3 ka, and ~5 ka. The ~1-ka final episode produced a variety of compositions including west- and north-flank mafic flows interspersed in time with fissure rhyolites erupted tangential to the volcano’s central caldera, including the youngest and most spectacular lava flow at the volcano, the ~950-yr-old compositionally zoned Glass Mountain flow. At ~3 ka, a north-flank basalt eruption was followed by an andesite eruption 27 km farther south that contains quenched basalt inclusions. The ~5-ka episode produced two caldera-focused dacitic eruptions. Quenched magmatic inclusions record evidence of intrusions that did not independently reach the surface. The inclusions are present in five andesitic, dacitic, and rhyolitic host lavas, and were erupted in each of the three episodes. Compositional and mineralogic evidence from mafic lavas and inclusions indicate that both tholeiitic (dry) and calcalkaline (wet) parental magmas were present. Petrologic evidence records the operation of complex, multi-stage processes including fractional crystallization, crustal assimilation, and magma mixing. Experimental evidence suggests that magmas were stored at 3 to 6 km depth prior to eruption, and that both wet and dry parental magmas were involved in generating the more silicic magmas. The broad distribution of eruptive events and the relative accessibility and good exposure of lavas, combined with physical and petrologic evidence for multiple and varied mafic inputs, has created an unusual opportunity to understand the workings of this large magmatic system. A combined total of more than 25 intrusive and extrusive events are indicated for late Holocene time. Plutonic inclusions, some with ages as young as Holocene, were also brought to the surface in five of the eruptions. All eruptions took place along northwest- to northeast-trending alignments of vents, reflecting the overall east-west extensional tectonic environment. The interaction of tectonism and volcanism is a dominant influence at this subduction-related volcano, located where the west edge of the extensional Basin and Range Province impinges on the Cascades arc. Ongoing subsidence focused at the central caldera has been documented along with geophysical evidence for a small magma body. This evidence, combined with the frequency of eruptive and intrusive activity in late Holocene time, an active geothermal system, and intermittent long-period seismic events indicate that the volcano is likely to erupt again.