So far in this century, six very large-magnitude earthquakes (MW ≥ 7.8) have ruptured separate portions of the subduction zone plate boundary of western South America along Ecuador, Peru, and Chile. Each source region had last experienced a very large earthquake from 74 to 261 y earlier. This history led to their designation in advance as seismic gaps with potential to host future large earthquakes. Deployments of geodetic and seismic monitoring instruments in several of the seismic gaps enhanced resolution of the subsequent faulting processes, revealing preevent patterns of geodetic slip deficit accumulation and heterogeneous coseismic slip on the megathrust fault. Localized regions of large slip, or asperities, appear to have influenced variability in how each source region ruptured relative to prior events, as repeated ruptures have had similar, but not identical slip distributions. We consider updated perspectives of seismic gaps, asperities, and geodetic locking to assess current very large earthquake hazard along the South American subduction zone, noting regions of particular concern in northern Ecuador and Colombia (1958/1906 rupture zone), southeastern Peru (southeasternmost 1868 rupture zone), north Chile (1877 rupture zone), and north-central Chile (1922 rupture zone) that have large geodetic slip deficit measurements and long intervals (from 64 to 154 y) since prior large events have struck those regions. Expanded geophysical measurements onshore and offshore in these seismic gaps may provide critical information about the strain cycle and fault stress buildup late in the seismic cycle in advance of the future great earthquakes that will eventually strike each region.