Aquatic ecosystems are increasingly threatened by multiple human-induced stressors associated with climate and anthropogenic changes, including warming, nutrient pollution, harmful algal blooms, hypoxia, and changes in CO2 and pH. These stressors may affect systems additively and synergistically but may also counteract each other. The resultant ecosystem changes occur rapidly, affecting both biotic and abiotic components and their interactions. Moreover, the complexity of interactions increases as one ascends the food web due to differing sensitivities and exposures among life stages and associated species interactions, such as competition and predation. There is also a need to further understand nontraditional food web interactions, such as mixotrophy, which is the ability to combine photosynthesis and feeding by a single organism. The complexity of these interactions and nontraditional food webs presents challenges to ecosystem modeling and management. Developing ecological models to understand multistressor effects is further challenged by the lack of sufficient data on the effects of interactive stressors across different trophic levels and the substantial variability in climate changes on regional scales. To obtain data on a broad suite of interactions, a nested set of experiments can be employed. Modular, coupled, multitrophic level models will provide the flexibility to explore the additive, amplified, propagated, antagonistic, and/or reduced effects that can emerge from the interactions of multiple stressors. Here, the stressors associated with eutrophication and climate change are reviewed, and then example systems from around the world are used to illustrate their complexity and how model scenarios can be used to examine potential future changes.