Mercury concentrations in Lake Champlain fish increased (2011-2017) for the first time in more than two decades. The increase, however, was not consistent among species or throughout the lake. Mercury concentrations in smallmouth bass and yellow perch from the three Main Lake segments increased significantly while concentrations in the eastern portions of the lake (Northeast Arm and Malletts Bay) remained unchanged or decreased; mercury concentrations in white perch remained unchanged. Factors examined to explain the increase included: atmospheric deposition, lake temperature, chlorophyll-a, fishery dynamics, lake flooding and loading of total suspended solids (TSS). This paper examines how each factor has changed between study periods and the spatial variability associated with the change. We hypothesize fishery dynamics, flooding and TSS loading may be partially responsible for the increase in fish mercury. Both growth efficiency and biomass of fish suggest mercury concentrations would increase in the Main Lake segments and decrease in the eastern portion of the lake. Additionally, two extreme climate events in 2011 resulted in extensive flooding and a four-fold increase in annual TSS loading, both potentially increasing biotic mercury with the impact varying spatially throughout the lake. Changes to the fishery and disturbance caused by extreme climatic events have increased biotic mercury and the processes responsible need further study to identify possible future scenarios in order to better protect human and wildlife health.