Climate refugia are anomalous "pockets" of spatially or temporally disjunct environmental conditions that buffer distinct flora and fauna against prevailing climatic conditions. Physiographic landscape features, such as large water bodies, can create these micro-to-macro-scale terrestrial habitats, such as the prevailing westerly winds across the Laurentian Great Lakes that create relatively cooler leeward conditions in spring and relatively warmer leeward conditions in autumn. The leeward Great Lakes climate effects create refugia (popularly known as a "fruit belt") favorable for fruit-bearing trees and shrubs. These fruit belt refugia owe their existence to seasonal inversions whereby spring cooling prevents early flower budding that leaves fruit trees susceptible to late spring killing frosts, and autumn warming prevents early killing frosts. With global climate change, however, warmer summers and milder winters, and corresponding warmer waters, might erode the leeward delaying effect on spring flowering, creating a paradoxical situation in which warming increases the risk of frost damage to plants. We evaluated the success of regional agriculture in the Great Lakes fruit belt to test our hypothesis that warmer spring climate (and concomitant warmer lake waters) correspond with degraded fruit production. We also examined long-term trends in Great Lakes climate conditions. We found that the cold-sensitive fruit tree (apple, grape, peach, and cherry) refugia were destabilized by relatively warmer springs. Moreover, we found several indicators that lake waters are warming across the Great Lakes, which portends negative consequences for agricultural and natural plant communities in the Great Lakes region and in similar "fruit belt" refugia worldwide.