The imperfect direct glacial record has led to the progressive extension of “initiation” of a continent-sized Antarctic ice sheet from 15 Ma to 33 Ma. Sea-level and deep-sea isotope records can be used to place constraints on the size and extent of Cenozoic Antarctic glaciation. Sea-level records indicate that small to medium sized (10-15 million cubic km), ephemeral ice sheets occurred during the greenhouse Late Cretaceous to middle Eocene. Global cooling with intermediate sized ice sheets began in the middle Eocene, culminating in the major Oi1 (33.5 Ma) oxygen isotope increase associated with growth of a continent-scale Antarctic ice sheet (25 x 106km3) and a 55 m sea-level fall. This large ice sheet became a driver, not only a response to climate change, causing increased latitudinal thermal gradients and a spinning up of the oceans that dramatically reorganized ocean circulation and chemistry.