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For millennia, natural disturbance regimes, including anthropogenic fire and hunting practices, have led to forest regeneration patterns that created a diversity of forest lands across the USA. But dramatic changes in climates, invasive species, and human population, and land use have created novel disturbance regimes that are causing challenges to securing desired natural regeneration. Climate is an ever-present background disturbance and determinant of species distribution. Changes in certain other factors such as large herbivore populations, wildfire, and pests modify forest composition and structure, and are common barriers to natural regeneration of desired species. Changes in long-standing disturbance regimes have led to the homogenization of forest landscape composition and structure. Today, forests have low regeneration potential and are low in resilience. They have reduced productivity and are prone to widespread health issues including severe forest mortality. In addition to epidemics of native invasive species due to climate change and availability of habitat at landscape scales, the continued introduction and spread of non-native pests and diseases are causing large-scale forest mortality. These ecological changes have cascading ecological consequences such as increases in severe wildfire, which pose new barriers to natural regeneration. Equally challenging are the barriers to natural regeneration that arise from social, political and economic factors. To address many of these issues requires active management that links all critical stages in the regeneration niche necessary for achieving desired regeneration to sustain forest development and production in a socially acceptable manner and economically viable market system.