UNESCO biosphere reserves are territories especially suited as laboratories for sustainability. They form a network of more than 600 units worldwide, intended to be key sites for harmonization of the nature-culture interface in the wide diversity of ecosystems existing on Earth. This mission is especially challenging in territories with high levels of land transformation and urbanization. The La Campana-Peñuelas Biosphere Reserve (BR) is one of these units: located in one of the world's conservation priority ecosystems, the Central Chilean Mediterranean ecoregion, it is at the same time one of the globally highly threatened spaces since the biota in this territory coexist with the most densely populated Chilean regions. This report deals with the main threats and land-use changes currently happening in the transition zone of La Campana-Peñuelas BR, which pose several challenges for the unit as an effective model of sustainability on a regional scale.