As the earth system moves to a novel state, model systems (experimental, observational, paleoecological) are needed to assess and improve the predictive accuracy of ecological models under environments with no contemporary analog. In recent years, we have intensively studied the no-analog plant associations and climates in eastern North America during the last deglaciation to better constrain their spatiotemporal distribution, test hypotheses about climatic and megaherbivory controls, and assess the accuracy of species- and community-level models. The formation of no-analog plant associations was asynchronous, beginning first in the south-central United States; at sites in the north-central United States, it is linked to declining megafaunal abundances. Insolation and temperature were more seasonal than present, creating climates currently nonexistent in North America, and shifting species–climate relationships for some taxa. These shifts pose a common challenge to empirical paleoclimatic reconstructions, species distribution models (SDMs), and conservation–optimization models based on SDMs. Steps forward include combining recent and paleoecological data to more fully describe species’ fundamental niches, employing community-level models to model shifts in species interactions under no-analog climates, and assimilating paleoecological data with mechanistic ecosystem models. Accurately modeling species interactions under novel environments remains a fundamental challenge for all forms of ecological models.