New data and review of classic sections from the Middle and Upper Ordovician North American Midcontinent in the Upper Mississippi Valley provide a refined picture of the age, stable isotope geochemistry, faunal composition, and—ultimately—origin of this epeiric ramp succession. Sequence stratigraphic analysis reveals a series of unconformity-bounded, genetically related facies packages. Shallowing and deepening trends are sometimes difficult to resolve due to a paucity of hydrodynamic indicators, yet unconformity surfaces are well marked by hardgrounds and confirmed by negative C-isotope spikes. Recent conodont biostratigraphy, new U-Pb radioisotopic ages for K-bentonites, and correlation of C-isotope profiles to global trends suggest that the succession spans the Darriwilian to Hirnantian epochs. Focus on Platteville to lower Galena Group strata (Sandbian to early Katian) provides a temporally high-resolution look at the onset and evolution of a long-term (>2 m.y.) positive carbon-isotope excursion, short-term perturbations in that record, and relationship to the preservation and diversity of the enclosed fauna and strata. Major changes in authigenic mineral suites and organic carbon content throughout the Upper Ordovician Upper Mississippi Valley suggest at least three major redox cycles. The combined evidence for globally recognized, positive carbon-isotope excursions coincident with these redox cycles, as well as high-frequency, sea-level fluctuations and successive faunal turnover events, suggests far-field responses to multiple global oceanic anoxic events.