Decentralized clinical trials (DCTs) move trial activities-such as recruitment, consent, delivery of the intervention, data collection and assessment of outcomes-away from traditional research sites to the homes or communities of patients. This participant-centered approach is accomplished through the use of digital health technology, remote monitoring, electronic data capture, and home- or community-based procedures. The advantage of DCTs may include broader trial recruitment pools with greater representativeness, reduced participant burden, greater operational efficiency and the ability to generate evidence in real-world settings. These features are particularly relevant in cardiovascular disease, which imposes a disproportionate population burden in regions where clinical trial centers are lacking. In this Perspective, we outline the essential components of the DCT ecosystem, discuss how DCTs can address key challenges in cardiovascular disease research, and using case examples, highlight operational and regulatory considerations in designing fully or partially (hybrid) decentralized trials. We also review the potential risks of DCTs and propose mitigation strategies to ensure high-quality, safe and reliable trial execution.