The optimal duration and type of antiplatelet therapy after implantation of a drug-eluting stent (DES) remains uncertain. At the time of the first-in-man implantation of the sirolimus DES in 1999, the protocol-defined dual antiplatelet therapy (DAPT) duration was only 2 months. Subsequently, DAPT duration was extended to 1 year on the basis of anecdotal historical data, and this practice was then incorporated into clinical guidelines. For >1 decade, trialists have sought to compare the safety and efficacy of abbreviated (<6 months) and prolonged (>12 months) DAPT regimens. However, the body of evidence is limited by the heterogeneity of end points, time of randomization, and bleeding criteria used in each trial. Pharmaceutical advances led to the introduction of new ADP-receptor antagonists, which are thought to be more effective than clopidogrel. The ADP-receptor antagonists moved the focus from the optimal duration of DAPT to the potential efficacy of single antiplatelet therapy after DES implantation. In this Review, we summarize the current evidence on the duration of DAPT and the risk of bleeding and adverse cardiac events after DES implantation, and describe the pitfalls of trial interpretation. The ongoing, prospective trials to test single antiplatelet therapy after DES implantation are also discussed.