Comparative physiology offers powerful approaches for developing causal, mechanistic explanations of shifts in biogeographic patterning occurring in concert with global change. These analyses can identify the cellular loci and intensities of stress-induced perturbation and generate predictions about ecosystem alterations in a changing world. Congeneric species adapted to different abiotic conditions offer excellent study systems for these purposes. Several findings have emerged from such comparative studies: 1) In aquatic and terrestrial habitats, the most heat-tolerant ectotherms may be most threatened by further increases in temperature, due to proximity of these species' thermal optima and tolerance limits to current maximal ambient temperatures and limited capacities for acclimatization to higher temperatures. 2) Cardiac function is a "weak link" in acute thermal tolerance. 3) Stress-induced changes in gene expression comprise a graded response involving genes linked to damage repair, lysis of irreversibly damaged molecules, and downregulation of cell proliferation. Transcriptomic and proteomic analyses provide "biomarkers" for diagnosing degrees of stress. 4) Different abiotic stresses may have synergistic or opposing effects on gene expression, a complexity needing consideration when developing integrated pictures of effects of global change. 5) Adaptation of proteins can result from one to a few amino acid substitutions, which can occur at many sites in a protein, a discovery with implications for rates of adaptive evolution. 6) Greater thermal tolerance of invasive species may favor their replacement of natives. 7) Losses of protein-coding genes and temperature-responsive gene regulatory abilities in stenothermal ectotherms of the Southern Ocean may lead to broad extinctions.