Platelets are crucial for preventing excessive blood loss at sites of injury by plugging holes in damaged blood vessels through thrombus formation. Platelet thrombi can, however, cause heart attack or stroke by blocking diseased vessels upon rupture of atherosclerotic plaques. Current anti-platelet therapy is not effective in all patients and carries a risk of bleeding. As such, a major goal in platelet research is to identify new drug targets to specifically inhibit platelets in disease processes. Tetraspanins are potential candidates because of their capacity to regulate other proteins in microdomains, and their defined roles in cell adhesion and signalling. In the last 6 years, analyses of tetraspanin-deficient mice have suggested that tetraspanins are indeed important for fine-tuning platelet responses. The future characterization of novel regulatory mechanisms in tetraspanin microdomains may lead to new drug targets for the prevention and treatment of heart attack and stroke.