Percutaneous coronary intervention with a drug-eluting stent is the most common mode of revascularization for coronary artery disease. However, restenosis rates remain high. Non-stent-based local drug delivery by a drug-coated balloon (DCB) has been investigated, as it leaves no metallic mesh. A DCB consists of a semicompliant balloon coated with antiproliferative agents encapsulated in a polymer matrix, which is released into the wall after inflation and contact with the intima. DCB have demonstrated effectiveness in treating in-stent restenosis. Clinical studies using DCB in de novo coronary artery disease have shown mixed results, with a major benefit in small-vessel disease. Differences in study results are not only due to variations in DCB technology but also to disparity in procedural approach, “leave nothing behind” or “combination therapy,” and vessel size. This review focuses on the available evidence from randomized trials and proposes a design for future clinical trials.