BACKGROUND Precision medicine, optimized interventions, and access to care are catchphrases for the future of behavioral treatments. Progress has been slow due to the dearth of clinical trials that (i) optimize interventions’ benefits; (ii) individually tailor interventions to meet individual patients’ needs and preferences; (iii) lead to rapid implementation after effectiveness is demonstrated. Two innovations have emerged to meet these challenges: fully remote trials and precision clinical trials. OBJECTIVE This paper provides a detailed description of an early-phase clinical trial, Mindful MyWay, designed to test online mindfulness training in older adults with depression. A smartphone app was developed to help coordinate the study, deliver the intervention, and evaluate the acceptability of the intervention, as well as predictors and outcomes of it. Consistent with the concept of fully remote trials, the study requires no in-person contact and can be conducted with participants anywhere in the US. Consistent with a precision medicine framework, the study assesses patients using high-frequency assessments of symptoms, cognitive performance, and patient preferences to both understand the individualized nature of treatment response and help individually tailor the intervention. METHODS The Mindful MyWay study delivers mindfulness education to older adults with depression. The curriculum parallels the Mindfulness-Based Stress Reduction (MBSR) curriculum, a structured group-based mindfulness training that is typically provided in person. The Healthy Mind Lab mHealth smartphone application (app) is downloaded from the Apple App Store. Participants receive reminders 4 times each day to complete brief smartphone-based assessments of depressive symptoms and cognitive performance, for 4 weeks both prior to and after completing the intervention. They also receive reminders each week to complete their web-based mindfulness video sessions. The intervention consists of an introduction video and 10 weekly mindfulness training sessions, with the expectation to practice mindfulness at home daily. The app also collects participant preference data throughout the 10-week intervention period; these high-frequency assessments identify participants’ individually dynamic preferences, towards a goal of individually optimizing the intervention in future iterations. RESULTS Participant recruitment and data collection began in March 2019. The final endpoint assessments will be collected in May 2022. The paper describes lessons learned regarding the critical role of early-phase testing prior to moving to a randomized trial. CONCLUSIONS The Mindful MyWay study is an exemplar of innovative clinical trial designs that use smartphone technology in behavioral and neuropsychiatric conditions. These include fully remote studies that can recruit throughout the US including hard-to-access areas and high-frequency data collection which is ideal for idiographic assessment and individualized intervention optimization. Our findings will be used to modify our methods and inform future randomized controlled trials within a precision medicine framework. CLINICALTRIAL NCT03922217; https://clinicaltrials.gov/ct2/show/NCT03922217 Clinicaltrials.gov (Initial release date 3/13/2019)