Gulf of Mexico ecosystems are interconnected by numerous physical and biological processes. As a result of the Deepwater Horizon (DWH) spill, some normal ecological processes including resource connectivity and trophic interactions and were damaged or broken. A considerable portion of post-DWH research has focused on higher levels of biological organization (i.e., populations, communities, and ecosystems) spanning at least four environments (onshore, coastal, open ocean, and deep benthos). Damage wrought by the oil spill and mitigation efforts varied considerably across ecosystems. Whereas all systems show prolonged impacts because of cascading effects that impacted functional connections within and between communities, deepsea and mesopelagic environments were particularly hard hit and have shown less resilience than shallow environments. In some environments, such as marshes or the deep-sea benthos, products from the spill are still biologically accessible. Some shallow ecosystems show signs of recovery, and populations of some species show resilience; however, a return to a “pre-spill” state is questionable. Importantly, habitats in which large amounts of energy flow through the ecosystem (marshes, coastal regions) recovered more quickly than low energy habitats (deep-sea benthos). Functional interactions between Gulf of Mexico systems are more complex and widespread than generally recognized. Moreover, ecosystems in the Gulf are subject to multiple stressors that can combine to impart greater, and less predictable, impacts. To help mitigate the effects of future insults, we identify four salient areas of research that should be addressed for each of the major environments within the Gulf of Mexico: establishing monitoring systems; quantifying coupling between Gulf ecosystems; developing criteria for assessing the “vulnerability” and “resilience” of species, communities, and ecosystems; and developing holistic predictive modeling.