Understanding the consequences of different management practices on vegetation phenology, forage production and quality, plant and microbial species composition, greenhouse gas emissions, and water budgets in tallgrass prairie systems is vital to identify best management practices. As part of the Southern Plains Long-Term Agroecosystem Research (SP-LTAR) grassland study, a long-term integrated Grassland-LivestOck Burning Experiment (iGLOBE) has been established with a cluster of six eddy covariance (EC) systems on differently managed (i.e., different burning and grazing regimes) native tallgrass prairie systems located in different landscape positions. The purpose of this paper is to describe this long-term experiment, report preliminary results on the responses of differently managed tallgrass prairies under variable climates using satellite remote sensing and EC data, and present future research directions. In general, vegetation greened-up and peaked early, and produced greater forage yields in burned years. However, drought impacts were greater in burned sites due to reductions in soil water availability by burning. The impact of grazing on vegetation phenology was confounded by several factors (e.g., cattle size, stocking rate, precipitation). Moreover, prairie systems located in different landscapes responded differently, especially in dry years due to differences in water availability. The strong correspondence between vegetation phenology and eddy fluxes was evidenced by strong linear relationships of greenness index (i.e., enhanced vegetation index) with evapotranspiration and gross primary production. Results indicate that impacts of climate and management practices on vegetation phenology may profoundly impact carbon and water budgets of tallgrass prairie. Interacting effects of multiple management practices and inter-annual climatic variability on the responses of tallgrass prairie highlight the necessity of establishing an innovative and comprehensive long-term experiment to address inconsistent responses of tallgrass prairie to different intensities, frequencies, timing, and duration of management practices, and to identify best management practices.