With a surface area of nearly 1,800 square kilometers, Lake Okeechobee is a prominent central feature of the South Florida aquatic ecosystem. The lake provides regional flood protection, supports a prized recreational fishery, provides habitat for migratory waterfowl and regional wading bird populations, and is a source of fresh water for irrigation, drinking, and restoration of downstream ecosystems. The main stressors on Lake Okeechobee are (1) large inputs of phosphorus from agricultural and other anthropogenic land uses in the watershed, (2) unnatural variation in water levels due to channelization of inflows and dike containment, and (3) rapid expansion of non-native plants. Ecological effects are complicated due to three distinct in-lake zones with different water chemistry, physical properties, and biota. A central pelagic zone has turbid, nutrient-rich water and phytoplankton dominance; a shallow south and western near-shore zone has submerged plant or phytoplankton dominance (at low vs. high water levels, respectively); and a western littoral zone is dominated by emergent wetland plants. Changes in water level influence the flow of nutrients between zones, thereby creating a synergistic effect between stressors. Under high water conditions, there is considerable advective transport of nutrients from the pelagic zone into the littoral zone. Under low water conditions, the littoral zone is cut off hydrologically and is a rainfall-driven oligotrophic wetland. Low water also facilitates drying and wildfires in the littoral zone, which in turn has an influence on expansion of non-native plants and recovery of native plants from buried seed banks. All of these factors influence fish, wading birds, and other animals, which depend on littoral and near-shore plant communities for nesting and foraging habitat. This paper describes our current knowledge of these complex processes, the lake's expected responses to ongoing and planned restoration programs, and key areas of uncertainty requiring future research.