The future of work embodies changes to the workplace, work, and workforce, which require additional occupational safety and health (OSH) stakeholder attention. Examples include workplace developments in organizational design, technological job displacement, and work arrangements; work advances in artificial intelligence, robotics, and technologies; and workforce changes in demographics, economic security, and skills. This paper presents the Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health's Future of Work Initiative; suggests an integrated approach to address worker safety, health, and well-being; introduces priority topics and subtopics that confer a framework for upcoming future of work research directions and resultant practical applications; and discusses preliminary next steps. All future of work issues impact one another. Future of work transformations are contingent upon each of the standalone factors discussed in this paper and their combined effects. Occupational safety and health stakeholders are becoming more aware of the significance and necessity of these factors for the workplace, work, and workforce to flourish, merely survive, or disappear altogether as the future evolves. The future of work offers numerous opportunities, while also presenting critical but not clearly understood difficulties, exposures, and hazards. It is the responsibility of OSH researchers and other partners to understand the implications of future of work scenarios to translate effective interventions into practice for employers safeguarding the safety, health, and well-being of their workers. © 2020 Wiley Periodicals LLC.