OBJECTIVE: There is growing interest in the NIOSH Total Worker Health program, specifically in the process of designing and implementing safer, health-promoting work and workplaces. A Total Worker Health (TWH) Research Methodology Workshop was convened to discuss research methods and future needs. METHODS: Twenty-six experts in occupational safety and health and related fields reviewed and discussed current methodological and measurement issues and those showing promise. RESULTS: TWH intervention studies face the same challenges as other workplace intervention studies and some unique ones. Examples are provided of different approaches and their applications to TWH intervention studies, and desired developments in the TWH literature. CONCLUSIONS: This report discusses and outlines principles important to building the TWH intervention research base. Rigorous, valid methodologic, and measurement approaches are needed for TWH intervention as well as for basic/etiologic, translational, and surveillance research.