So far this century, six Mw > 7.8 earthquakes have ruptured portions of the subduction zone plate boundary of western South America along Ecuador, Peru, and Chile. Each source region had a history of prior great earthquakes and had not ruptured in recent decades. Their identification as seismic gaps, with the potential to host future great megathrust earthquakes, helped guide the selection of several regions for intensive earthquake research and monitoring.  Reevaluations of older instrumentally recorded earthquakes, as well as paleoseismic studies of historic events have reduced the epistemic uncertainty in characterizing great earthquake rupture in the region.  Comparisons of great earthquakes that have occurred along the same portion of the seismic zone have also demonstrated the range of aleatory variability between successive ruptures. Installation of dense seismic and geodetic monitoring arrays significantly enhanced the resolution of subsequent faulting processes.  Patterns of heterogeneous pre-seismic and co-seismic deformation reflect spatial variations in the frictional properties of the megathrust.  Localized areas of high coseismic moment release have been correlated with regions of high interseismic coupling or asperities.  The persistent nature of these asperities and interactions between adjacent asperities on the megathrust influences the variability of great earthquake ruptures from cycle to cycle. Observations from the recent sequence of great earthquakes provides an opportunity to update the current perspective on earthquake hazard for the remaining seismic gaps along the South American subduction zone.