High-resolution continuous core material, geophysical measurements, and hundreds of archived core descriptions enabled to identify 13 Late Pleistocene Rhine-Meuse sedimentary units in the infill of the southern part of the North Sea basin (the Netherlands, northwestern Europe). This sediment record and a large set of Optical Stimulated Luminescence dates, 14C dates and biostratigraphical data, allowed to establish detailed relationships between climate change, sea-level oscillation, glaciation history and the sedimentary development of the Rhine fluvial system during the last glacial cycle (Marine Isotope Stages 5e-2, Eemian-Weichselian). A well-preserved Eemian sediment record was encountered as the infill of a Late Saalian (MIS6) subglacial basin. Part of this record reflects groundwater rise controlled (fine-grained) sedimentation as a result of postglacial (early) Eemian sea-level rise. It shows strong analogy to developments known from the Holocene Rhine-Meuse delta. Outside of the glacial depressions near coastal deposits are only fragmentarily preserved. The Early Glacial Rhine sediment record is dominated by organic debris and peat layers, marking landscape stability and low fluvial activity. Part of this record may have been formed under near coastal conditions. Significant amounts of reworked marine biomarkers in the lag-deposits of Early Pleniglacial (MIS4) fluvial systems indicate that this period is characterized by extensive reworking of older (MIS5) near-coastal sediments. Despite the marked Early Pleniglacial climatic cooling, input of new sediment from the drainage basin was relatively low, a feature that is related to the presence of regolith protective relic soil complexes in the basin. During the early Middle Pleniglacial, a major Rhine avulsion indicates the system was in an aggrading mode and that sediment supply into the lower reaches of the Rhine had strongly increased. This increase in sediment supply coincided with the timing of major climate cooling that occurred from ∼50 to 45 ka onwards. The increase in sediment supply is related to final breakup of the soil complexes in the drainage basin. After ∼24 ka, a strong input of coarse-grained gravelly sediments was observed which indicates a strong increase in physical weathering processes and periglacial-controlled supply of bedload sediment in the catchment. A time delay between climate change (∼30 ka) and channel belt aggradation (<24 ka), is explained as a result of transport path length between source and sink and/or effects of higher continental runoff rates after 22 ka. The Late Middle Pleniglacial, Late Pleniglacial and Lateglacial Rhine-Meuse record testifies for strong influence of glacio-isostatic-controlled differential upwarping of the study area. Glacio-isostatic-controlled forebulge upwarping and lateral valley tilting is shown to have deflected Rhine-Meuse channel belts after 35 ka. Glacio-isostatic upwarping is seen as the main cause for strong incision during the first phase of the Late Pleniglacial (30-24 ka). At later stage glacio-isostatic-controlled incision was overruled due to high climate-controlled sediment input from the catchment and probably initial glacio-isostatic subsidence. Migration of channel belts towards the direction of the former centre of glacio-isostatic uplift indicates that glacio-isostacy influenced Rhine-Meuse paleogeography until far into the Lateglacial.