Ischemic cardiovascular events represent the leading cause of mortality and morbidity worldwide, and platelet aggregation and thrombus formation are the main effectors of acute arterial ischemic events. Although antiplatelet therapy is the cornerstone of antithrombotic treatment of ischemic cardiovascular disorders, available antiplatelet agents have less than satisfactory efficacy; thus, the identification of novel potential target candidates for antiplatelet therapy is highly warranted. Recent evidence suggests that several molecules that amplify the aggregation response of platelets to activating stimuli, which are either released by platelets (potentiating molecules) or present in the milieu before platelets get activated (primers), play a major role in pathologic thrombus formation without being significantly involved in primary haemostasis. These molecules appear to be a particularly appealing novel potential pharmacologic target for antiplatelet therapy. Here, we review the present knowledge on some molecules acting as potentiators or primers of platelet activation and discuss their possible pharmacologic modulation for antithrombotic purposes.