Mountain social-ecological systems (MtSES) are vital to humanity, providing ecosystem services to over half the planet's human population. Despite their importance, there has been no global assessment of threats to MtSES, even as they face unprecedented challenges to their sustainability. With survey data from 57 MtSES sites worldwide, we test a conceptual model of the types and scales of stressors and ecosystem services in MtSES and explore their distinct configurations according to their primary economic orientation and land use. We find that MtSES worldwide are experiencing both gradual and abrupt climatic, economic, and governance changes, with policies made by outsiders as the most ubiquitous challenge. Mountains that support primarily subsistence-oriented livelihoods, especially agropastoral systems, deliver abundant services but are also most at risk. Moreover, transitions from subsistence- to market-oriented economies are often accompanied by increased physical connectedness, reduced diversity of cross-scale ecosystem services, lowered importance of local knowledge, and shifting vulnerabilities to threats. Addressing the complex challenges facing MtSES and catalyzing transformations to MtSES sustainability will require cross-scale partnerships among researchers, stakeholders, and decision makers to jointly identify desired futures and adaptation pathways, assess trade-offs in prioritizing ecosystem services, and share best practices for sustainability. These transdisciplinary approaches will allow local stakeholders, researchers, and practitioners to jointly address MtSES knowledge gaps while simultaneously focusing on critical issues of poverty and food security.