The recent decoupling of deforestation and soybean production has raised optimistic expectations towards enhanced land use sustainability in the South-Eastern Amazon agricultural frontier. Nonetheless, assessing land use sustainability implies not only the consideration of how agricultural activities affect natural ecosystems but also how they impact on society and how society can cope with them. We review some of the forthcoming challenges that the agricultural sector should address to confirm its significant progress towards land use sustainability. Firstly, we assess the recent efforts to adopt environmentally friendly practices with regard to the ongoing intensification process mainly based on double cropping systems. Secondly, while rapid agricultural development has brought major social advances, we evidence a recent trend towards a decoupling of soy production and the Human Development Index at municipality level. We then put this result into perspective considering that the trend towards agricultural intensification based on the use of large amounts of agrochemicals could lead to major health concerns which are still too rarely considered. Finally, we discuss how the recent efficient policies to contain deforestation in the Amazon can cause indirect land use changes in the Brazilian Cerrados and in African Savannas, thus potentially leading to an “illusion of preservation” at global scale. We conclude that new indicators involving social sciences are necessary to better address the complexity of land use sustainability on the still very dynamic agricultural frontier in the South-Eastern Amazon.