The MESA (Multi-Ethnic Study of Atherosclerosis) has been highly successful in investigating the prevalence, characteristics, and progression of subclinical cardiovascular disease (CVD) in a multiethnic American cohort of adult men and women free of CVD at baseline. MESA has also championed the use of novel biomarkers and emerging imaging techniques for the assessment of subclinical CVD and has created an extensive set of data that continues to fuel dozens of ongoing analyses. Insights from MESA include the first demonstration of ethnic differences in coronary artery calcification and its association with subclinical disease progression and incident CVD. Other findings include ethnic differences in the prevalence of pharmacological, behavioral, and lifestyle interventions for the primary prevention of CVD. MESA has also shown the association between residential neighborhood characteristics and behavioral and biomedical risk factors for CVD. This vast amount of data documenting ethnic differences in progression of subclinical CVD, diabetes, kidney disease, and pulmonary disease contrasts sharply with the relative scarcity of specific information that can pave the way for the elimination of racial and ethnic disparities. Intervention research, however, goes beyond the original objectives of MESA and other observational studies. The time has now come to build on the legacy of MESA by supporting rigorous intervention research that informs clinical and public health strategies as well as policy and environmental changes for eliminating racial and ethnic disparities in CVD and other chronic diseases and advancing the health of multiethnic communities.