Current trajectories of global change may lead to regime shifts at regional scales, driving coupled human-environment systems to highly degraded states in terms of biodiversity, ecosystem services, and human well-being. For business-as-usual socioeconomic development pathways, regime shifts are projected to occur within the next several decades, to be difficult to reverse, and to have regional- to global-scale impacts on human society. We provide an overview of ecosystem, socioeconomic, and biophysical mechanisms mediating regime shifts and illustrate how these interact at regional scales by aggregation, synergy, and spreading processes. We give detailed examples of interactions for terrestrial ecosystems of central South America and for marine and coastal ecosystems of Southeast Asia. This analysis suggests that degradation of biodiversity and ecosystem services over the twenty-first century could be far greater than was previously predicted. We identify key policy and management opportunities at regional to global scales to avoid these shifts.