The All Of Us Research Program (AOURP) is a historic effort to enable 21st century biomedical research that will benefit all persons in the USA. The inclusion of at least 1 million volunteers into one study is not only unprecedented in scale, but also sets new standards in reaching every individual, regardless of race and ethnicity, age, geography, or health status. This will power genetic studies of health and well-being, which will eventually deliver more precise treatments and personalized medications. Already, early examples of this approach are apparent in the form of advanced cancer treatments and genetic therapies. Large and easily accessible datasets are essential to support the research needed for such breakthrough advances. In return, AOURP participants will have access to their genetic data, receive medically relevant personalized feedback, and gain insights into other aspects of their own personal health. A specific strength of the AOURP is the role of Regional Medical Centers (RMC), which provide their experienced staff and faculty, their resources, and their trusted relationships with patients and communities, to engage, enroll, and retain participants for the AOURP study. We have formed a consortium of such RMCs in the States of Florida, Georgia, and the Territory of Puerto Rico. We call this the SouthEast Enrollment Center (SEEC-2), led by University of Miami, University of Florida Gainesville, Morehouse School of Medicine, Emory University, and the University of Puerto Rico Comprehensive Cancer Center. These five prestigious academic regional medical centers are further allied with several public and private hospital systems and are working with dozens of regional partner organization to allow every individual in this geographic area access to the AOURP. Over the past five years, the SEEC team has registered more than 51,000 individuals and fully enrolled nearly 40,000 core participants into the AOURP study. At a closer look, these participants truly represent the diversity of people living in this region. More than 67% identify with a race or ethnicity that is historically not well represented in medical research studies, thus potentially missing out on the benefits of new treatments. Approximately 25% are of older age, and 18% have disabilities; together 93% of SEEC participants belong to the category of Underrepresented in Biomedical Research (UBR). More than 44% of SEEC enrolled participants have actively followed up with the Program after their initial enrollment activities. The next phase, SEEC-2, will help push the national participant count to over 1 million AOURP individuals. We will more than double the above engagement and enrollment numbers, make AOURP a well-known mainstay in our communities, retain the majority of core participants, and foster the adoption of the researcher workbench. We plan to significantly expand our enrollment options and to implement novel activities, in order to make it easier for individuals to join AOURP. Examples include mobile enrollment with buses, partnerships with smaller hospital systems, and the development of regional networks of community organizations for outreach and engagement. We will expand digital and remote enrollment options for individuals unable to travel to our enrollment sites. Our community centered trained staff will use multiple measures of communication to keep participants engaged, including marketing, web and social media presence, phone calls, web calls, and assistance with ride share travel. Retention is already above 50% in several of the SEEC-2 regions. We will actively retain at least 55% of all SEEC participants, most of them UBR, by Year 5 of SEEC-2. The Southeastern region of the United States is home to a growing population of 36 million people, characterized by a rich history, a unique climate, and unmatched diversity. SEEC-2 investigators and institutions provide access to this diverse and distinctive population helping to achieve the overall goals of the national Program. With nearly six years of experience and a large, well-trained, and motivated team, SEEC-2 will continue our successful engagement, enrollment, and retention strategies in the coming five years. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions for the opioid crisis and overdose epidemic, including opioid use disorder and stimulant use disorder. The NIH HEAL Initiative bolsters research across NIH to address the national opioid public health crisis and improve treatment for opioid misuse and addiction.