Climate change will affect temperature extremes and averages, and hyposaline conditions in coastal areas due to extreme precipitation events and oceanic pH. How climate change will push species close to, or beyond, their physiological tolerance limits as well as change the limits of their biogeographic ranges can probably be investigated best in species that have already responded to climate change and whose distribution ranges are currently in flux. Blue mussels provide such a study system, with the invading warm-adapted Mediterranean Mytilus galloprovincialis having replaced the native more cold-adapted Mytilus trossulus from the southern part of its range in southern California over the past century, possibly due to climate change. However, freshwater input may prevent the latter species from expanding further north. We used a proteomics approach to characterize the responses of the two congeners to acute heat stress, chronic thermal acclimation, and hyposaline stress. In addition, we investigated the proteomic changes in response to decreasing seawater pH in another bivalve, the eastern oyster Crassostrea virginica. The results suggest that reactive oxygen species (ROS) are a common costressor during environmental stress, including oceanic acidification, and possibly cause modifications of cytoskeletal elements. All stressors disrupted protein homeostasis, indicated by the induction of molecular chaperones and, in the case of acute heat stress, proteasome isoforms, possibly due both to protein denaturation directly by the stressor and to the production of ROS. Acute stress by heat and hyposalinity changed several small G-proteins implicated in cytoskeletal modifications and vesicular transport, respectively. Changes in abundance of proteins involved in energy metabolism and ROS scavenging further suggest a possible trade-off during acute and chronic stress from heat and cold between ROS-generating NADH-producing pathways and ROS-scavenging NADPH-producing pathways, especially through the reaction of NADPH-dependent isocitrate dehydrogenase and the pentose-phosphate pathway. Some of the proteomic changes may not constitute de novo protein synthesis but rather shifts in abundance of isoforms differing in posttranslational modifications, specifically acetylation by a NAD-dependent deacetylase (sirtuin). Interspecific differences suggest that these processes set physiological tolerance limits and thereby contribute to recent biogeographic shifts in range, possibly caused by climate change.