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The long-term complications associated with stent implantation for the treatment of coronary and peripheral artery disease have prompted a search for more conservative treatments, and a ‘leave nothing behind’ strategy. Drug-coated balloons are an attractive alternative that combine the advantages of balloon angioplasty with inhibition of neointimal proliferation and restenosis. Paclitaxel has so far been the drug of choice in balloon coating, given its high lipophilicity and local tissue retention. Still, its use is limited by a narrow therapeutic window and safety concerns. Sirolimus-coated balloons entered the drug-coated balloon arena late because of the need to use specific technologies to overcome pharmacokinetic limitations. Their use was initially tested in in-stent restenosis and small-calibre native vessels, demonstrating results that overlapped with those obtained with paclitaxel-coated balloons in terms of efficacy. New indications for sirolimus-coated balloon angioplasty are emerging, such as acute coronary syndromes, coronary bifurcations, peripheral and coronary medium- to large-calibre native vessels, critical limb ischaemia, vasculogenic erectile dysfunction, and dysfunctional arteriovenous fistulas. Data in these areas are still limited to small, non-randomised studies, showing encouraging results.