Modern earthquake activity in central and eastern North America (CENA) generally is thought to occur as reactivations in the modern stress field of pre-existing crustal zones of weakness, but the identification of which specific faults can be reactivated in strong earthquakes and how often such strong earthquakes might occur is not very advanced. There is a growing acceptance of the idea that areas of spatially clustered and locally higher rates of modern small earthquakes in CENA might be places where stronger past earthquakes took place. The sizes of these spatial clusters may be related to the magnitudes of the past earthquakes, with more extensive spatial clusters corresponding to larger past earthquakes. In CENA many of the earthquakes occur in crust that underwent Mesozoic or younger rifting, including in the offshore Atlantic Margin areas. Also, many of the modern small CENA earthquakes have been centered near or on faults not associated with a Mesozoic basin but nevertheless were active during Mesozoic time. These observations suggest that all of the Mesozoic basins and faults that were active during Mesozoic or later time should be considered as potential source zones of future strong earthquakes. If much of the modern CENA seismicity is comprised of late aftershocks of past strong earthquakes, then the rates of the modern seismicity may not be a good indicator of the probabilities of future strong earthquakes. For example, the rate of M≥7 earthquakes in CENA over historic time is greater than expected based on extrapolations from the rates of the smaller earthquake activity. Furthermore, the number of spatial clusters of small earthquakes in CENA also suggests more M≥7 earthquakes in the past few thousand years than would be expected from modern seismicity rates. For CENA, continued paleoseismological investigations looking for evidence of past strong earthquakes combined with detailed analyses of past and future seismicity clusters throughout CENA are needed to help address these important questions concerning the seismic hazard of this highly populated region.