Regulatory proposals to limit tobacco product constituent levels pose questions and challenges for leaf production. Each constituent has its own biological or chemical synthesis and physiological pathway determined by the tobacco variety and commonly influenced by leaf production variables such as geological factors, crop growing conditions and cultural practices. Further, constituent levels often differ across the anatomy of the plant and the age of the leaf material. Research targeting the impact of these variables is critical in determining potential mechanisms to moderate constituent levels in leaf. The challenge is increasingly complex when attempting to reduce multiple, naturally occurring constituents simultaneously. It is important to also consider the relationship between levels in leaf and those in final consumer products, especially if analysing constituent levels in ratio to nicotine yield as suggested in some regulatory proposals. With knowledge of pathways of constituent synthesis and/or accumulation, various strategies can be employed to influence toxicant levels during leaf production, each of which would require research and development supported by analytical testing and feasibility assessments. Strategies could include cultivar selection, new cultivar development, cultural practice modification or other supply chain changes. The selection and implementation of toxicant limits requires a science-based, stepwise approach, supported by validated methods, robust sets of testing data and changes in leaf production supported by farmer dialogue and field extension services. Potential impacts include changes in farm production yields and costs, which need to be analysed and addressed to minimize negative impacts to farmers and suppliers. Given the number of targeted constituents in various chemical families, there may arise situations where modifications to leaf production may require balancing opposing impacts to two or more toxicant levels. This fact necessitates responsible limit setting addressing risk, feasibility and uncertainty associated with an agricultural crop, in a biological system which is often impacted by an ever changing environment.