Determining the relationship between environmental and evolutionary change is a research problem as old as evolutionary biology, and one that has occupied many paleobiologists. The long and rich Paleogene macrofossil record of the U.S. Gulf Coastal Plain (GCP) would seem an excellent laboratory for pursuing this question, for stratigraphy and taxonomy have been worked out in great detail. Yet despite the long history of study, obtaining answers that are not underdetermined in these assemblages is a major challenge. Any such effort must deal with several basic substantive and methodological issues, even before working out the potential effects on biotas of changes in major paleoenvironmental variables such as sea level, temperature, and productivity. These include evolutionary tempo and mode, completeness of the record, nature of stratigraphic and event boundaries, obtaining accurate and sufficiently detailed paleoenvironmental data, and distinguishing evolutionary from biogeographic change. To facilitate this line of research in the Gulf, we are compiling the most complete record to date of stable-isotope-based paleotemperature data through the Paleogene sequence, based both on the literature and on new analyses. Preliminary comparison of these new data and existing sea-level curves with first and last appearances of GCP mollusk species suggests that there is only a weak overall correlation, implying that the physical environment alone, as represented by these variables within the Gulf setting, may not be the primary driver for all evolutionary change in these faunas. Potentially fruitful lines of research might focus now on individual clade responses to environmental changes, and on how faunas respond ecologically to such perturbation. A review of previous and ongoing work on evolution of macrofaunas in the Paleogene of the GCP indicates that few studies have investigated the role of the environment in affecting evolutionary tempo and mode in individual lineages, although the potential for such research is considerable.