Following percutaneous coronary intervention (PCI), an initial course of dual antiplatelet therapy (DAPT) with aspirin and a P2Y{}_{12} inhibitor (P2Y{}_{12}-i) is recommended to minimize the risk of thrombotic complications. After the initial period of DAPT, antiplatelet monotherapy, usually consisting of aspirin, is administered for long-term secondary prevention. However, over the last few years there has been accruing evidence on P2Y{}_{12}-i monotherapy, both in the acute (i.e., post-PCI; after a brief period of DAPT, transitioning to monotherapy before six or 12 months in patients with chronic or acute coronary syndrome, respectively) and chronic (i.e., long-term secondary prevention; after completion of six or 12 months of DAPT, in patients with chronic or acute coronary syndrome, respectively) settings. In aggregate, most studies of short DAPT with transition to P2Y{}_{12}-i monotherapy showed a reduced risk of bleeding complications, without any significant increase in ischemic events as compared to standard DAPT. On the other hand, the evidence on long-term P2Y{}_{12}-i monotherapy is scarce, but results from a randomized trial showed that clopidogrel monotherapy outperformed aspirin monotherapy in terms of net benefit, ischemic events and bleeding. Antiplatelet therapy is also recommended for patients undergoing PCI and with an established indication for long-term oral anticoagulation (OAC). In this scenario, a brief period of triple therapy (i.e., aspirin, P2Y{}_{12}-i and OAC) is followed by a course of dual antithrombotic therapy (usually with P2Y{}_{12}-i and OAC) and ultimately by lifelong OAC alone. European and American guidelines have been recently updated to provide new recommendations on antithrombotic therapy, including the endorsement of P2Y{}_{12}-i monotherapy in different settings. However, some areas of uncertainty still remain and further randomized investigations are ongoing to fulfil current gaps in knowledge. In this review, we assess the current knowledge and evidence on P2Y{}_{12}-i monotherapy for the early and long-term secondary prevention in patients undergoing PCI, and explore upcoming research and future directions in the field.