High-resolution data collected over the past 60 years by a single family of Siberian scientists on Lake Baikal reveal significant warming of surface waters and long-term changes in the basal food web of the world's largest, most ancient lake. Attaining depths over 1.6 km, Lake Baikal is the deepest and most voluminous of the world's great lakes. Increases in average water temperature (1.21 °C since 1946), chlorophyll a (300% since 1979), and an influential group of zooplankton grazers (335% increase in cladocerans since 1946) may have important implications for nutrient cycling and food web dynamics. Results from multivariate autoregressive (MAR) modeling suggest that cladocerans increased strongly in response to temperature but not to algal biomass, and cladocerans depressed some algal resources without observable fertilization effects. Changes in Lake Baikal are particularly significant as an integrated signal of long-term regional warming, because this lake is expected to be among those most resistant to climate change due to its tremendous volume. These findings highlight the importance of accessible, long-term monitoring data for understanding ecosystem response to large-scale stressors such as climate change.