Giant clams are threatened by overexploitation for human consumption, their valuable shells and the aquarium trade. Consequently, these iconic megafauna are extinct in some former areas of their range and included in the IUCN Red List of Threatened Species and CITES list. Now, giant clams are also threatened by rapid environmental change from both a suite of local- to regional-scale stressors and global change, including ocean heating and acidification. The interplay between local- to regional-scale and global-scale drivers is likely to cause an array of lethal and sub-lethal effects, potentially limiting giant clam depth distribution on coral reefs and decreasing suitable habitat area within natural ranges. International efforts urgently need to reduce CO2 emissions to avoid lethal and sub-lethal effects on giant clams. Meanwhile, knowledge of ecological and physiological responses to local–regional and global stressors could play a critical role in the conservation of these species through rapid environmental change. Further work on how biological responses translate into habitat requirements as global change progresses, selective breeding for resilience, the capacity for rapid adaptive responses of the giant clam holobiont, and valuing tourism potential may help improve the prospects of these charismatic megafauna over coming decades.