Jim Zachos's research interests encompass a wide variety of problems related to the biological, chemical, and climatic evolution of late Cretaceous and Cenozoic oceans. He is a paleoceanographer who measures the chemical compositions of fossils to reconstruct past changes in marine temperatures, ocean circulation, continental ice-volume, marine productivity, and carbon cycling. His research is oriented toward identifying the mechanisms responsible for driving long and short-term changes in global climate.

Zachos and his students are currently participating in several projects directed towards understanding the nature of rapid and extreme climate transitions in earth history. These projects involve the application of stable isotopes and trace metal ratios to reconstruct past climates and ocean chemistry for several episodes of extreme climates including the Paleocene-Eocene Thermal Maximum (~55 mya), the middle and early Eocene Climatic Optimums (~48 & 52 mya respectively), as well as the subsequent long term cooling trends. Zachos and his students are also measuring the isotope and trace metal ratios of marine microfossils to establish the approximate timing and extent of continental glaciations during the Oligocene and Miocene, from 15 to 35 million years ago. They have documented evidence of pronounced climatic response to periodic changes in Earth's orbit.