The tallgrass prairie ecosystem has experienced a dramatic reduction over the past 150 yr. This reduction has impacted the abundance of native grassland species, including milkweeds (Asclepias). We used two long-term (27 yr) data sets to examine how fire, grazing, and nutrient addition shape milkweed abundance in tallgrass prairie. We compared these results to those of a greenhouse experiment that varied nutrient levels in the absence of competition, herbivory, and mutualistic relationships. Asclepias species exhibited broad patterns in response to burning regimes that did not include grazing, but experienced more species-specific patterns in other combinations. Asclepias syriaca was the only species to increase in abundance in plots that included burning and nutrient addition. In the greenhouse we found that nitrogen significantly increased biomass, while no effect of phosphorus was detected. These results indicate that A. syriaca will do best in settings with high nutrient loads, low competition, and no grazers. These characteristics define a small portion of the tallgrass prairie but exemplify modern agricultural settings, which have replaced prairies. However, other milkweeds examined did not share this pattern, which indicates that milkweed species will respond differently when exposed to agricultural settings, with some less able to cope with land conversion to pasture or row-crop agriculture.