To understand interactions of lake physical characteristics, trophic dynamics and climate in Lago Maggiore, we compare longterm limnological and meteorological monitoring data and results from sediment cores. We include analyses of nutrients, pigments, diatoms and cladoceran microfossils. Over the past decades, caloric content increased. Eutrophication from the 1960s to early 1980s was followed by oligotrophication. DDTs, PCBs and Hg showed high contamination in the '60s, compared to point source inputs in the '90s. Algal biomass was predicted by total pigments and some algal specific carotenoids. Following nutrient enrichment, Chydorus sphaericus, and total abundance of cladocerans changed inversely with trophic status. Fewer large Daphnia since the late '80s matched an increase in with subfossil Eubosmina mucro lengths. Both were explained by the 10-fold increase in Bythotrephes longimanus from 1987 to 1993, when an increase of its mean annual population density occurred during warmer winter and springs. Bythotrephes remained abundant and further increased during the following 10 years as water temperature increased. We conclude that warmer water affects food chains indirectly by changing habitat use and predator-prey interactions. Relative abundances of Daphnia and its peak population density in the warm year of the oligotrophic period (2003) were close to the record from the mesotrophic period in 1982, supporting the hypothesis that warming can produce a eutrophication-like signal. The study illustrates the complexity of biological responses to synchronous changes in multiple drivers (e.g., eutrophication, fish introduction, ban of fish harvesting, chemical pollution, and climate) and, despite this complexity, how Lago Maggiore responded to multiple stressors.