Patients with coronary artery disease (CAD) presenting with acute coronary syndrome or undergoing coronary stenting are indicated to treatment with dual antiplatelet therapy (DAPT) combining aspirin with a P2Y12 receptor inhibitor. The management of patients with CAD who present with a complex clinical profile due to multiple comorbidities, and/or undergoing complex interventional procedures, remains challenging as a high risk for both ischemic and bleeding events is often present; hence, the risk-benefit balance on the optimal DAPT duration is difficult to evaluate. The complexity of antiplatelet therapy in CAD patients is due to the fact that this complexity embraces several aspects: the coronary anatomy, the number of vascular districts at risk for atherothrombosis, and patient comorbidities, including global frailty. Recent randomized and epidemiological studies have highlighted subgroups that could benefit from prolonged antithrombotic treatment, as well as frail patients, who may be better suited to a shorter course of therapy. We provide an overview of the current knowledge regarding treatment with DAPT, along with suggestions on its management.