New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.