Dual-antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor is recommended for use as first-line therapy in patients with acute coronary syndromes (ACS) who undergo high-risk percutaneous coronary intervention. However, revascularization may not be a beneficial option for some subgroups of patients with ACS. This includes a broad spectrum of lower risk patients as well as high-risk patients with numerous previous revascularizations and those who are at high risk for complications, such as those with complex coronary anatomy and co-morbidities such as diabetes mellitus, chronic kidney disease, or advanced age and frailty. For such patients, there remains an unmet need for evaluation of alternatives to the currently recommended treatment options. Notably, there is a paucity of prospective data regarding management approaches to medically managed patients with ACS. Thus, this group of medically managed patients with ACS would benefit from inclusion in clinical trials investigating therapeutic options for patients not scheduled to undergo invasive procedures, such as those who are targeted for pharmacologic management only. In conclusion, in this review, the investigators revisit data from clinical studies of dual-antiplatelet therapy in ACS to highlight areas of unmet need in antiplatelet therapy in patients with ACS and to examine the use of newer agents in subgroups, such as medically managed patients with ACS, that would potentially benefit from more potent platelet inhibition after ACS.