The global political economy is facing extreme challenges against a backdrop of large-scale expansion of human and domestic animal populations and related impacts on the biosphere. Significant global socio-ecological changes have occurred in the period of a single lifetime, driven by increased technology and access to physical and biological resources through open markets and globalization. Current resource consumption rates are not sustainable and ecological tipping points are being reached and one of the indicators of these may be a changing balance between hosts and pathogens. A period of extraordinary progress in reducing infection risk and disease impact on humans and domestic animals in the 20th Century is reversing in the 21st, but not always and not everywhere. Drivers for this shift are discussed in terms of demographics, agroecology, biodiversity decline and loss of resilience in ecosystems, climate change and increasing interconnectedness between species globally. Causality of disease emergence remains highly speculative, but patterns and data are emerging to commend a precautionary approach, while reassessing our global political, social and economic systems.