Humans are causing profound and rapid transformations of Earth's ecosystems to the extent that we are threatening the sustainability of the biosphere. The development of long-term socio-ecological research, integrating monitoring and experiments at the ecosystem scale, will be essential to detect, prevent, and mitigate the degradation of ecosystems at regional and global scales. To strengthen and expand the nascent Long-Term Socio-ecological Research (LTSER) Network of Chile, we need to integrate efforts of academic, private, and government institutions. A strong long-term research and monitoring program will require a conceptual framework and a set of relevant, comparative, and trans-disciplinary questions. Here, we identify these relevant questions and propose a conceptual framework for the Chilean LTSER Network. Further, we provide guidelines for its organization and consider the needs for infrastructure and funding to sustain the operation of a national network of ecological observatories.