This chapter explores the co-evolution of the Southern Ocean (SO) and Antarctic Ice Sheet (AIS) from the Eocene-Oligocene Transition (EOT, ~34 million years ago, Ma) through to the Pleistocene (the last 2.6 Ma). The EOT was a period of major tectonically-induced climatic change and development of the SO. The evolution of the topography of the Antarctic continent during the Oligocene and Miocene periods (34-35 Ma) played an important role in the establishment of polar conditions, the expansion of a continental-scale ice sheet, and its interplay with the SO. The subsequent Pliocene and Pleistocene periods (last 5.3 Ma) were times of marked global cooling and the evolution of the SO-Antarctic system during which the Earth transitioned towards bi-polar glaciation, with ice sheet expansion in both hemispheres. Lastly, we discuss the role of interhemispheric heat exchange via atmospheric and oceanic processes to explain warmer-than-preindustrial conditions within some warm interglacial periods and their impact on the SO and AIS.<p></p>