We compared long-term change in two lake districts, one in a forested rural setting and the other in an urbanizing agricultural region, using lakes as sentinel ecosystems. Human population growth and land-use change are important drivers of ecosystem change in both regions. Biotic changes such as habitat loss, species invasions, and poorer fishing were prevalent in the rural region, and lake hydrology and biogeochemistry responded to climate trends and landscape position. Similar biotic changes occurred in the urbanizing agricultural region, where human-caused changes in hydrology and biogeochemistry had conspicuous effects. Feedbacks among ecosystem dynamics, human uses, economics, social dynamics, and policy and practice are fundamental to understanding change in these lake districts. Sustained support for interdisciplinary collaboration is essential to build understanding of regional change.