The Paleocene-Eocene Thermal Maximum (PETM; ca. 55.8 Ma) is thought to coincide with a profound but entirely transient change among nannoplankton communities throughout the ocean. Here we explore the ecology of nannoplankton during the PETM by using multivariate analyses of a global data set that is based upon the distribution of taxa in time and space. We use these results, coupled with stable isotope data and geochemical modeling, to reinterpret the ecology of key genera. The results of the multivariate analyses suggest that the community was perturbed significantly in coastal and high-latitudes sites compared to the open ocean, and the relative influence of temperature and nutrient availability on the assemblage varies regionally. The open ocean became more stratified and less productive during the PETM and the oligotrophic assemblage responded primarily to changes in nutrient availability. Alternatively, assemblages at the equator and in the Southern Ocean responded to temperature more than to nutrient reduction. In addition, the assemblage change at the PETM was not merely transient—there is evidence of adaptation and a long-term change in the nannoplankton community that persists after the PETM and results in the disappearance of a high-latitude assemblage. The long-term effect on communities caused by transient warming during the PETM has implications for modern-day climate change, suggesting similar permanent changes to nannoplankton community structure as the oceans warm.