Reconstruction of the vertical motion history of Crete and Karpathos (southeastern Aegean region, Greece) from the Messinian to Recent revealed a previously poorly documented late Messinian phase of strong subsidence with rates of 50-100 cm/k.y. followed by stasis during the first 250 k.y. of the Pliocene and then by uplift of 500-700 m during the late early to early middle Pliocene. Uplift continued up to Recent albeit at a slower pace and at different rates in different areas. The lower Pliocene in Crete and Karpathos is characterized by widespread occurrences of mass-wasting deposits, which were emplaced over a period of time spanning the first 1.35 m.y. of the Pliocene. The origin of these mass-wasting deposits has long been enigmatic but is here related to uplift which started in Crete as early as ca 5 Ma. It is suggested that the beginning uplift following strong subsidence of various fault blocks until late in the Messinian is related to the onset of south Aegean strike-slip faulting. We postulate that small-scale tilting of fault blocks by transtensional strike-slip faulting and increased seismic activity generated slope failures and subsequent sliding of poorly cemented lower Pliocene and uppermost Messinian Lago Mare sediments overlying the terminal Miocene erosional unconformity. The absence of mass-wasting deposits after 3.98 Ma, while uplift continued, is most likely the result of progressive compaction and cementation of the increasingly deeper buried Lago Mare and lower Pliocene sediments, thereby preventing slope failure to a depth of the terminal Mocene unconformity. Matuses in some places in Crete and on Karpathos, however, indicate that slope failures continued to occur although on a smaller scale and less frequent than before. Connecting the change from subsidence to uplift in the earliest Pliocene with the onset of left-lateral, strike-slip tectonics in the southeastern Aegean arc would make this major strike-slip system much older (by ∼2 m.y.) than the generally accepted age of middle to late Pliocene. A recently postulated scenario of "Subduction Transform Edge Propagator" (STEP) faulting to explain the south Aegean strike-slip system predicts rates, distribution, and amount of uplift as rebound to south-westward retreat of the subducted slab along a transform fault zone that is in line with our findings on Crete and Karpathos and explains the absence of compressional structures associated with the uplift, as well as the ongoing southwestward motion of Crete. © 2008 Geological Society of America.