The use of aspirin is considered the "gold standard" for the decrease of major adverse cardiovascular events in patients with atherosclerosis, including peripheral arterial disease (PAD), whereas a dual-antiplatelet regimen with aspirin and clopidogrel is usually indicated for such patients after angioplasty and stent deployment. However, a substantial number of subsequent adverse events still occur, even in patients who receive double-antiplatelet therapy. The "high on-treatment platelet reactivity" (HTPR) phenomenon has been lately recognized and plays a major role in the management of patients with PAD. Greater and more rapid inhibition of platelet aggregation has become the goal for new antiplatelet agents with the expectation of further improving outcomes for percutaneous intervention for PAD. The purpose of this review article is to highlight current evidence regarding the prevalence, aetiology, and clinical implications of HTPR in PAD as well as to discuss the possibilities of novel alternative antiplatelet regiments.