The paleoearthquake activity on the Spili Fault is examined using a novel methodology that combines measurements of Rare Earth Elements (REE) and of in situ cosmogenic 36Cl on the exhumed fault scarp. Data show that the Spili Fault is active and has generated a minimum of five large-magnitude earthquakes over the last ~16500 years. The timing and, to a lesser degree, the slip-size of the identified paleoearthquakes was highly variable. Specifically, the two most recent events occurred between 100 and 900 years BP producing a cumulative displacement of 3.5 meters. The timing of the three older paleoearthquakes is constraint at 7300, 16300 and 16500 years BP with slip sizes of 2.5, 1.2 and 1.8 meters, respectively. The magnitude of the earthquakes that produced the measured co-seismic displacements, ranges from M 6.3-7.3 while the average earthquake recurrence interval on the Spili Fault is about 4200 years. The above data suggest that the Spili is among the most active faults on Crete and its earthquake parameters may be incorporated into the National Seismic Hazard Model.