Prolonged dual antiplatelet therapy is the cornerstone of the therapy after drug-eluting stent implantation. However, it is associated with risks and side-effects, such as bleeding events, which can negatively affect overall prognosis. Moreover, premature antiplatelet therapy discontinuation is not uncommon both in clinical trials and in clinical practice. It can lead to serious short-term and long-term complications, such as stent thrombosis, acute myocardial infarction and death. Although lack of patient's motivation can be regarded as an important cause of drug withdrawal, recent studies showed that medical decisions can be an even more frequent cause of premature discontinuation. The management of a patient with a coronary stent, undergoing surgery, is challenging and might lead to antiplatelet therapy withdrawal. In the present article, adherence and side-effects of antiplatelet therapy will be reviewed, also focusing on new antiplatelet drugs, such as prasugrel and ticagrelor. Furthermore, pharmacological interactions (e.g. proton pump inhibitors) as well as other causes of drug discontinuation will be addressed, particularly focusing on their prognostic and practical implications.