This inter-disciplinary collection explores significant land-use changes in South Africa’s semi-arid Karoo region and their implications for social justice and the environment, across different scales. It brings together recent scholarship by established and younger researchers, in both the social and the natural sciences, to examine the ways in which the Karoo is being reconfigured as a new ‘resource frontier’ and the tensions and contestations that result. Along with ongoing mining, major investments in astronomy (notably the Square Kilometre Array radio telescope), in renewable and non-renewable sources of energy (solar, wind, potential shale-gas mining), in biodiversity conservation and commercial game farming are reshaping land use and authority in this vast and long-marginalised area. While promising significant benefits to society at large, these developments are built on older histories of dispossession and extractivism – histories that many Karoo residents fear are being reproduced in new forms today. Collectively these dynamics place this unique region at the centre of national and global concerns around climate change, the politics of knowledge production, the conservation of threatened biodiversity, and the meaning and possibility of sustainable development. These issues are explored through a series of case studies of selected developments, complemented by chapters providing more historical context and general overviews. While challenging perceptions of this region as a peripheral wasteland, this collection raises conceptual and policy questions that resonate far beyond the Karoo itself. It also highlights the importance of interdisciplinary collaboration in research aimed not only at understanding but also at responding appropriately to the mounting challenges of our time.