Summary. Platelet integrin αIIbβ3 plays an essential role in thrombus formation through interactions with adhesive ligands. Successful parenteral blockade of these interactions has validated αIIbβ3 as a therapeutic target in cardiovascular medicine. However, oral αIIbβ3 antagonists have not been successful and there is an unmet need for more effective anti-platelet drugs. Growing evidence points to the cytoplasmic tails of αIIb and β3, and the β3 tail in particular, as scaffolds for intracellular proteins that mediate inside-out signaling and regulate αIIbβ3 affinity for ligands. Intracellular protein interactions with the integrin cytoplasmic tails also regulate outside-in signals to the actin cytoskeleton. Here we focus on recent studies that illustrate the relevance of the β3 cytoplasmic tail as a regulatory scaffold in vivo. We speculate that this scaffold or its interacting proteins may serve as therapeutic targets for the development of future anti-thrombotic drugs.