<p>The U.S. Midwest exemplifies anthropogenically driven losses of soil organic carbon (SOC) following conversion of the North American prairie to agricultural over the past two centuries. The current near-equilibrium SOC of the agriculturally dominated Midwest is a new phase for this landscape—and stands to inform future trajectories of SOC. Understanding historical SOC change in the U.S. Midwest is particularly important because it is a global hotspot of both crop production and SOC deficits, and thus where unrealized SOC increase potential affords co-benefits to future agroecosystem productivity. Here we overview shifts in SOC equilibrium at the landscape level in the U.S. Midwest in three major phases: (1) post-glacial SOC accumulation, (2) rapid SOC loss to a lower equilibrium following agricultural land use, and (3) future potential trajectories assuming continued agricultural land use. For each phase, we evaluate changes in SOC as a dynamic equilibrium resulting from a balance of inputs and outputs, and synthesize climatic, ecological, and agricultural drivers of changes in carbon input and output to illustrate the magnitude and timescales of SOC change from past to present. Agricultural practices that may partially restore SOC to varying extents are discussed. While few are likely to fully recoup SOC stocks to the level of prairies, socioeconomics will likely pose greater challenges to rebuilding SOC—and to what extent is ideal is itself subjective. We conclude by proposing four major areas for future research relevant to SOC and carbon cycling in the U.S. Midwest: the amount and fate of relic prairie-derived SOC, the role of subsurface SOC, potentially large but irreversible loss of SIC, and water management impacts on SOC.</p>