The platelet integrin GPIIb/IIIa plays an essential role in thrombus formation through interactions with adhesive ligands and has emerged as a primary target for the development of anti-thrombotic agents. Receptor activation is under strict control, with activators, inhibitors, and signalling mechanisms controlling its conformation. Structural biology research has produced high-resolution images defining the ligand binding site at the atomic level. Successful blockade of this ligand binding has validated GPIIb/IIIa as a therapeutic target in cardiovascular medicine. GPIIb/IIIa inhibitors were the first rationally designed anti-platelet agents and have been used effectively in a wide variety of clinical scenarios including unstable angina, myocardial infarction, and high risk percutaneous coronary interventions with and without intracoronary stenting. Three inhibitors (abciximab, eptifibatide, and tirofiban) are currently licensed for human use. Surprisingly, oral GPIIb/IIIa antagonists have not been successful and there is an unmet need for effective anti-GPIIb/IIIa drugs that cause less bleeding problems and that can be orally applied. Here we review our current knowledge about GPIIb/IIIa structure, signalling pathways and receptor function, the benefits and limitations of current GPIIb/IIIa blockers and we take a look forward how the lessons learned from the mixture of success and failure of GPIIb/IIIa blocker development can be transformed in new and better GPIIb/IIIa blockers.