James Zachos's investigations of the Paleocene-Eocene Thermal Maximum and other major climate shifts in Earth's past are highly relevant to understanding how human activities are driving modern-day global climate change. A study he coauthored in 2016 shows that the current rate at which carbon is being released into the atmosphere is unprecedented in at least the past 66 million years.

Zachos is a fellow of the American Academy of Arts and Sciences, American Geophysical Union, California Academy of Sciences, and Geological Society of America. He received the 2016 Milutin Milankovic Medal from the European Geosciences Union. His work has been widely featured in media coverage of climate change, including articles in the New Yorker and National Geographic magazines.