ABSTRACT Significant transitions at midlife can be positive for some, but many also experience emotional challenges, physical health declines, and high stress in adapting to new social roles. Yet, health and functioning at midlife have received less attention compared to older ages because disease and disability remain relatively rare. This combination of growing health challenges and low rates of disability points to opportunities for intervention to prevent and delay more serious illness and impairment. This study addresses important gaps in knowledge to better capitalize on these opportunities. Little is known about how midlife may be different for those now in their 40s and 50s?often labeled Generation X?who are much more diverse demographically and in their family formation and education/career paths than prior generations. Most existing midlife research has also focused on relatively narrow health outcomes with little consideration of the interplay of physical and mental health and functioning in work and civic life. Recent studies showing significant health declines in new midlife cohorts additionally underscore the need for a focus on disparities and sociodemographic differences in midlife health and mechanisms to explain them, particularly increasing alcohol misuse and its central role in midlife health risks. This study brings strengths to examining these issues by drawing on existing longitudinal data from the Seattle Social Development Project (SSDP) and collecting new data in early midlife. SSDP has followed a gender-balanced, multiethnic, and socioeconomically diverse panel of 808 participants across 15 waves from age 10 to 39 with high retention. Data include theory-guided assessments of the social environment throughout; unique longitudinal assessments of neighborhood environments that integrate self-report, Census, and GIS measures; and longitudinal measures of alcohol and other substance use and disorder, mental and physical health, and functioning in work, community, and civic life. New data augment and extend existing measures into midlife and enable the examination of midlife-specific experiences. The study aims are to examine (1) how sociodemographic statuses and transitions among those now entering midlife influence comorbid health outcomes in early midlife; (2) how alcohol use, misuse and related behaviors during midlife influence midlife health, as well as the influence of life course trajectories of alcohol use and misuse leading up to midlife; (3) how malleable social and neighborhood environmental factors influence alcohol use and misuse over the life course and, in turn, affect midlife health; and to (4a) examine the long-term malleability of social environmental factors from early adolescence to midlife by testing the mechanisms of a childhood intervention (embedded in the existing study); and (4b) identify promising adult intervention targets by conducting focus groups with participants to help design and tailor prevention programs. With guidance from empirical findings and participants themselves, the goal of the study is to provide researchers and health practitioners with specific recommendations for preventive interventions addressing public health priorities for midlife adults.