Work characteristics and worker well-being are inextricably connected. In particular, the characteristics of work organization shape and perpetuate occupational stress, which contributes to worker mental health and well-being outcomes. Consequently, the importance of understanding and addressing connections between work organization, occupational stress, and mental health and well-being—the focus of this Special Issue—increasingly demand attention from those affected by these issues. Thus, focusing on these issues in the long-haul truck driver (LHTD) sector as an illustrative example, the purpose of this commentary is as follows: (1) to outline current research approaches and the extant knowledge base regarding the connections between work organization, occupational stress, and mental health; (2) to provide an overview of current intervention strategies and public policy solutions associated with the current knowledge base to protect and promote worker mental health and well-being; and (3) to propose a two-pronged agenda for advancing research and prevention for workers during the 21st century. It is anticipated that this commentary, and this Special Issue more broadly, will both echo numerous other calls for building knowledge and engaging in this area and motivate further research within complementary current and novel research frameworks.