Antiplatelet therapies are a cornerstone in the prevention and treatment of major thrombotic cardiovascular diseases. Over the years, significant advancements in the development and approval of antiplatelet agents have substantially reduced morbidity and mortality associated with these conditions. Current antiplatelet therapies target cyclooxygenase-1, P2Y12 receptor, integrin αIIbβ3, phosphodiesterases, and protease-activated receptor (PAR) 1. However, limitations such as insufficient efficacy and a high incidence of bleeding complications remain significant challenges. Recent progress in pharmaceutical design has facilitated the development of novel agents targeting established pathways. Further, elucidating the role of critical platelet receptors, such as G-protein coupled receptor (GPR) 31 and GPR56, and advances in understanding molecular mechanisms of platelets in hemostasis and thrombosis have identified new therapeutic targets. These include innovative approaches targeting glycoprotein (GP) VI, GPIb, PAR4, prostacyclin receptor, and 12-lipoxygenase, several of which have progressed to clinical trials. This chapter explores novel pharmacological strategies for platelet inhibition and discusses results from preclinical and clinical studies. The goal of antiplatelet therapy is the development of agents that selectively inhibit pathological thrombus formation while preserving normal hemostasis. The development of safe and efficacious novel antiplatelet therapies can improve the treatment and prevention of thrombotic cardiovascular diseases.