As a consequence of the COVID-19 pandemic, the number of decentralized clinical trials, trials conducted in whole or in part at locations other than traditional clinical trial sites, significantly increased. While these trials have the potential advantage of access, participant centricity, convenience, lower costs, and efficiency, they also raise a number of important ethical and practical concerns. Here we focus on a number of those concerns, including participant safety, privacy and confidentiality, remote consent, digital access and proficiency, and trial oversight. Awareness of these ethical complexities will help foster the development of processes and cooperative solutions to promote safe, ethical trials going forward, optimized to decrease burden and increase access for all participants.