The southern Cape of South Africa hosts a remarkably rich Middle Stone Age (MSA) archaeological record. Many of the associated caves and rock shelters are coastal sites, which contain evidence for varied occupational intensity and marine resource use, along with signs of notable landscape, environmental, and ecological change. Here, we review and synthesize evidence for Quaternary landscape and climatic change of relevance to the southern Cape MSA. We seek to highlight the available data of most relevance to the analysis and interpretation of the region’s archaeological record, as well as critical data that are lacking. The southern Cape MSA occupation spans the full range of glacial-interglacial conditions (i.e., 170–55 ka). It witnessed marked changes in coastal landscape dynamics, which although driven largely by global eustatic sea level changes, were modulated by local-scale, often inherited, geological constraints. These prevent simple extrapolations and generalizations concerning paleolandscape change. Such changes, including pulses of coastal dune activity, will have directly influenced resource availability around the region’s archaeological sites. Evidence for paleoclimatic change is apparent, but it is scarce and difficult to interpret. It is likely, however that due to the same diversity of rainfall sources influencing the region today, compared to parts of the continental interior, the southern Cape climate was relatively equable throughout the last 150 kyr. The region’s paleoecology, particularly in relation to the coastal plains exposed during sea level lowstands, is a key element missing in attempts to synthesize and model the resources available to occupants of this region. Technology, settlement, and subsistence probably changed in response to these paleoclimate/landscape adjustments, but improvements in baseline archaeological and paleoenvironmental data are required to strengthen models of ecosystem variation and human behavioral response through the MSA.