OBJECTIVE: To improve engagement and retention of a cohort that reflects the US population within the Research Program, we created and implemented an innovation infrastructure and initiatives. PARTICIPANTS AND METHODS: participant laboratories (APLs) established innovation-specific processes to rapidly ideate, select, implement, and evaluate cost-effective innovative initiatives, while mitigating risks. This was done within 4 priority areas: accelerating enrollment, enhancing engagement and retention, improving biospecimen collection, and broadening data types. Participants within the Research Program were engaged in this research between April 6, 2022 and May 6, 2024. RESULTS: We present a summary of APL processes and portfolio along with 5 specific initiatives that rapidly tested innovative ways to increase task completion and broaden biospecimen submission accessibility. Each initiative's cost-benefit profile was evaluated by a committee of program leadership. Findings include the following: (1) offering compensation increased task completion, the degree of which was dependent on the context and amount of compensation; and (2) adding evening and weekend blood donation appointment times and distributing saliva collection kits through community partners increased donations from participants who have been historically underrepresented in biomedical research. On average, program staff predicted initiative effect sizes would be more than double their actual effect. CONCLUSION: We found that large research studies can rapidly innovate to meet program goals, including a focus on diversity. We identified specific strategies and tactics to improve health research engagement and retention, with a focus on historically underrepresented in biomedical research communities, which can be used by numerous health research studies.