Knowledge of the state of stress in the Earth’s crust is key to understanding the forces and processes responsible for earthquakes. Historically, low rates of natural seismicity in the central and eastern United States have complicated efforts to understand intraplate stress, but recent improvements in seismic networks and the spread of human-induced seismicity have greatly improved data coverage. Here we compile a nationwide stress map based on formal inversions of focal mechanisms that challenges the idea that deformation in continental interiors is driven primarily by broad, uniform stress fields derived from distant plate boundaries. Despite plate-boundary compression, extension dominates roughly half of the continent, and second-order forces related to lithospheric structure appear to control extension directions. We also show that the states of stress in several active eastern United States seismic zones differ significantly from surrounding areas and that these anomalies cannot be explained by transient processes, suggesting that earthquakes are focused by persistent, locally-derived sources of stress. Such spatially variable intraplate stress appears to justify the current, spatially variable estimates of seismic hazard. Future work to quantify sources of stress, stressing-rate magnitudes, and their relationship with strain and earthquake rates could allow prospective mapping of intraplate hazard.