The Amoco 1 Eischeid well (Sec. 6, T83N, R35W, Carroll County, Iowa) was the first significant well drilled along the flank of the Iowa horst, providing an opportunity to evaluate the stratigraphic and structural history of the enigmatic Mid-Continent rift system of the United States. New thermal-history data obtained from cutting and core samples show that three paleothermal events affected the drilled section at the Amoco 1 Eischeid well. Results show that three significant cooling events occurred sometime between 300 and 200, 70 and 50, and 35 and 10 Ma. The first of these events was associated with a high paleogeothermal gradient (35°C/km), demonstrably greater than the present-day value (16°C/km). These new results provide direct evidence of a significantly higher paleogeothermal gradient (and by inference, higher heat flow) during the Paleozoic. In addition, results show that maximum maturity of the rich Precambrian source, the Nonesuch Shale (equivalent), was reached during the 300–200-Ma event and not 600–700 m.y. earlier as previously proposed. Previous work has been significantly influenced by the view that the craton was relatively stable or behaved uniformly throughout the Phanerozoic. Previous models impose a Proterozoic time of generation and entrapment for any Precambrian source intervals. With recognition of significant Phanerozoic heating events, the opportunity for later generation emerges, thus reducing the preservation time and increasing the probability of entrapment and preservation needed for exploration success in the region. Furthermore, these events mapped at the Mid-Continent rift system may be of great regional extent and correlative in time to other well-known events along the North American plate margins (e.g., Alleghanian, Laramide, Ancestral Rockies orogenies), thus offering insights to new possible exploration targets within the rift, perhaps indicative of deep-seated processes in the mantle beneath the North American craton during the Phanerozoic.