Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) represents the treatment of choice for the majority of patients with coronary artery disease. While currently available DES, in addition to physiological support, has failed to show the non-inferiority to coronary artery bypass grafting (CABG) in terms of cumulative incidence of clinical events over the short-term follow-up. Studies have also shown that DES is associated with an increased risk of target vessel revascularization compared to CABG after long-term follow-up. Drug-coated balloons (DCB) have been shown to provide clinically significant benefits in the management of in-stent restenosis and diffuse coronary artery disease, as well as small coronary artery lesions. The aim of this review was to describe the inherent technical limitations of DES and highlight the potential advantages of PCI with DCB for long-term outcomes and potentially demonstrate its non-inferiority to CABG. Currently, ongoing studies will provide more information and help to understand if a blended therapy of DCB+DES can match the performance of CABG in the need for revascularization in more complex patients.