Platelets are dynamic blood cells that form life-threatening thrombi in response to a variety of pathological conditions such as atherosclerosis, diabetes, metastatic cancer, sickle cell disease and obesity. These thrombi can lead directly to myocardial infarction (MI), stroke and other thrombotic events that contribute to over a million deaths every year in the United States. Even though multiple, effective drugs have been developed to combat these pathologies by antagonizing platelet receptors and their ligands, clinical use of these drugs can result in serious bleeding consequences. With the advent of increasingly powerful and accessible systems biology approaches, however, new opportunities are available to identify novel platelet targets and elucidate potentially safer antiplatelet strategies. Here we provide an overview of some of these exciting systems approaches ranging from genomics to aptamer discovery and emphasize the importance of identifying and exploiting novel platelet targets for therapeutic benefit.