We collected 43 km of high resolution seismic reflection profiles from a 14.5-hectare lake in the central Florida sinkhole district and data from three adjacent boreholes to determine the relationship between falling lake levels and the underlying karst stratigraphy. The lake is separated from karstified Paleogene to early Neogene carbonates by 65-80 m of siliciclastic sands and clays. The carbonate and clastic strata include three aquifer systems separated by clay-confining units: a surficial aquifer system (fine to medium quartz sand in the upper 20-30 m), the 25-35 m thick intermediate aquifer system (in Neogene siliciclastics), and the highly permeable upper Floridan aquifer system in Paleogene to early Neogene limestones. Hydraulic connection between these aquifer systems is indicated by superjacent karst structures throughout the section. Collapse zones of up to 1000 m in diameter and > 50 m depth extend downward from a prominent Middle Miocene unconformity into Oligocene and Upper Eocene limestones. Smaller sinkholes (30-100 m diameter, 10-25 m depth) are present in Middle to Late Neogene clays, sands, and carbonates and extend downward to or below the Middle Miocene unconformity. Filled and open shafts (30-40 m diameter; 10-25 m depth) ring the lake margin and overlie subsurface karst features. The large collapse zones are localized along a northeast-southwest line in the northern ponds and disrupt or deform Neogene to Quaternary strata and at least 50 m of the underlying Paleogene carbonate rocks. The timing and vertical distribution of karst structures are used to formulate a four-stage model that emphasizes stratigraphic and hydrogeologic co-evolution. (1) Fracture-selective shallow karst features formed on Paleogene/early Neogene carbonates. (2) Widespread karstification was limited by deposition of Middle Miocene clays, but vertical karst propagation continued and was focused because of the topographic effects of antecedent karst. (3) Groundwater heads increase with the deposition of thick sequences of clastics over the semipermeable clays during Middle and Late Neogene time. The higher water table and groundwater heads allowed the accumulation of acidic, organic-rich soils and chemically aggressive waters that percolated down to Paleogene carbonates via localized karst features. (4) After sufficient subsurface dissolution, the Paleogene carbonates collapsed, causing disruption and deformation of overlying strata. The seismic profiles document an episodic, vertically progressive karst that allows localized vertical leakage through the clay-confining units. The spatial and temporal karst distribution is a result of deposition of sediments with different permeabilities during high sea levels and enhanced karst dissolution during low sea levels. Recent decreases in the potentiometric elevation of the Floridan Aquifer System simulates a sea-level lowstand, suggesting that karst dissolution will increase in frequency and magnitude.