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Climate change is a well-recognized threat to lake ecosystems and, although there likely exists geographic variation in the sensitivity of lakes to climate, broad-scale, long-term studies are needed to understand this variation. Further, the potential mediating role of local to regional ecological context on these responses is not well documented. In this study, we examined relationships between climate and water clarity in 365 lakes from 1981 to 2010 in two distinct regions in the northeastern and midwestern United States. We asked (1) How do climate-water-clarity relationships vary across watersheds and between two geographic regions? and (2) Do certain characteristics make some lakes more climate sensitive than others? We found strong differences in climate-water-clarity relationships both within and across the two regions. For example, in the northeastern region, water clarity was often negatively correlated with summer precipitation (median correlation = -0.32, n = 160 lakes), but was not correlated with summer average maximum temperature (median correlation = 0.09, n = 205 lakes). In the midwestern region, water clarity was not related to summer precipitation (median correlation = -0.04), but was often negatively correlated with summer average maximum temperature (median correlation = -0.18). There were few strong relationships between local and sub-regional ecological context and a lake's sensitivity to climate. For example, ecological context variables explained just 16-18% of variation in summer precipitation sensitivity, which was most related to total phosphorus, chlorophyll a, lake depth, and hydrology in both regions. Sensitivity to summer maximum temperature was even less predictable in both regions, with 4% or less of variation explained using all ecological context variables. Overall, we identified differences in the climate sensitivity of lakes across regions and found that local and sub-regional ecological context weakly influences the sensitivity of lakes to climate. Our findings suggest that local to regional drivers may combine to influence the sensitivity of lake ecosystems to climate change, and that sensitivities among lakes are highly variable within and across regions. This variability suggests that lakes are sensitive to different aspects of climate change (temperature vs. precipitation) and that responses of lakes to climate are heterogeneous and complex.