Abstract: Ongoing deforestation in the Brazilian Amazon is the outcome of an explicit federal project to occupy, integrate, and “modernize” the region. Although there have been isolated periods of deforestation control, most recently between 2004 and 2012, the overall trajectory of the region since the colonial period has been one of forest loss and degradation. Addressing this challenge is especially urgent in the context of adverse climate-ecology feedbacks and tipping points. Here we describe the trends and outcomes of deforestation and degradation in the Amazon. We then highlight how historical development paradigms and policies have helped to cement the land use activities and structural lock-ins that underpin deforestation and degradation. We emphasize how the grounds for establishing a more sustainable economy in the Amazon were never consolidated, leading to a situation where forest conservation and development remain dependent on external programs—punitive measures against deforestation and fire and public social programs. This situation makes progress toward a forest transition(arresting forest loss and degradation and restoring forest landscapes) highly vulnerable to changes in political leadership, private sector engagement, and global market signals. After summarizing these challenges, we present a suite of measures that collectively could be transformational to helping overcome destructive path dependencies in the region. These include innovations in agricultural management, improved forest governance through landscape approaches, developing a local forest economy, sustainable peri-urbanization, and the empowerment of women and youth. These initiatives must be inclusive and equitable, enabling the participation and empowerment of local communities, particularly indigenous groups who have faced numerous historical injustices and are increasingly under threat by current politics.