Treatment of chronic total occlusions (CTOs) is referred to as the last frontier of percutaneous coronary interventions and is currently performed in 10% to 20% of procedures. Improved outcomes with newer generation drug-eluting stents require further research. The TARGET CTO trial (NCT03040934) is a prospective, multicenter, randomized, noninferiority trial that plans to randomize 196 subjects (1:1) to either a newer-generation sirolimus target-eluting stent or an everolimus-eluting stent. Patients are candidates if they present with at least 1 CTO lesion in a native coronary artery with a diameter of ≥2.50 mm to ≤4.00 mm and a length of <100 mm. In addition, 44 subjects will participate in an optical coherence tomography (OCT) substudy. Clinical follow-up is planned up to 5 years after stent implantation. Angiographic follow-up is planned at 12 months, whereas OCT will be obtained after the procedure, at 3 and 12 months. The primary end point is in-stent late lumen loss by quantitative coronary angiography at 12 months. The key secondary end point is neointimal thickness by OCT at 3 months. Imaging end points are assessed by an independent core lab. Clinical end points are adjudicated by an independent clinical events committee. The TARGET CTO trial compares a sirolimus target-eluting stent with an everolimus-eluting stent for management of CTOs according to contemporary interventional practices. The primary angiographic end points will be reported at 12 months and clinical follow-up will continue for up to 5 years.