The Meso-Hellenic Basin (MHB) is a large, narrow and elongated basin containing up to c. 5 km of Cenozoic sediments, which partially covers the tectonic boundary between the external, western zones (Pindos) and the internal, eastern zones (Pelagonian) of the Hellenide fold-and-thrust belt. New results, based on micropaleontologic, sedimentologic and tectonic field data from the southern half of the MHB, suggest that the MHB originated as a forearc basin during the first stages of a subduction (Pindos basin), and evolved into a true piggyback basin as a result of the collision of thicker crustal units (Gavrovo-Tripolitsa). The late Eocene forearc stage is marked by sharply transgressive, deep sea turbiditic deposition on the subsiding active margin. At this stage, large scale structures of the Pelagonian basement (i.e. the newly defined “Pelagonian Indentor”) control deposition and location of two main subsiding sub-basins located on both sides of the MHB. The Eocene-Oligocene boundary corresponds to a brief tectonic inversion of the basin, at the onset of collision (main compressive event). The true piggyback stage (Oligo-Miocene) is recorded by slope deposition and dominated by gravity processes (from slumped, fine grained turbidites to conglomeratic fan- or Gilbert-deltas). The new elongated geometry of the MHB is controlled by the underthrusted, NNW-SSE trending, thick external zones. During this stage, the locus of subsidence migrates in the same direction (eastward) as underthrusting. This subsidence, favoured by thick dense ophiolitic basement, is attributed to basal tectonic erosion of the upper Pelagonian unit while the tectonic structures of this upper unit control the stepped migration of subsidence. Growing duplexes in the Gavrovo underthrusted unit, which formed local uplifts, were mainly situated on the eastern side of the subsiding areas and associated with normal faulting (late Oligocene–early Miocene). They constituted new loads that could also have been responsible for minor but widespread lithospheric subsidence. The development of the local and regional uplifts explains the basin evolution toward shallow, dominantly conglomeratic deposits and its final emergence at the end of the middle Miocene. This trend toward emersion is emphasized by the late Miocene global sea-level fall. The MHB was subsequently overprinted by neotectonic deformation associated with the development of a continental basin (Ptolemais) and uplift attributed to the evolution of the Olympos structure that developed further east as the underthrusting moved in this direction. These results demonstrate that the Meso-Hellenic Basin evolves as a large scale piggyback Basin and that its sedimentary infill is largely controled by tectonic activity rather than only eustatic sea-level variations.