Plant-made pharmaceuticals (PMPs) offer great promise as efficacious and cost-effective products for the treatment of human and animal disease. The benefits of this technology must be balanced against potential health and environmental risks that may be associated with its use. Risks associated with human and animal health and environmental impacts of PMPs can be minimized through adoption of production confinement and product channelling processes that have stringencies consistent with the degree of hazard or uncertainty associated with a specific product. Risk assessment considers the probability for harm to occur as a consequence of exposure in the production, processing, and use of a given PMP. Risk assessment focused on the intended uses of PMPs involves manufacturing and medicinal use scenarios that consider workers and consumers of the PMP; whereas the risk assessment for unintended occurrence in food or feeds considers a differing nature of exposure (in terms of the route, intensity, frequency and duration of exposure). The consequences of intended and unintended use both must be considered and managed for comprehensive understanding of risk. Regardless, because PMPs presently have no provision for regulatory tolerances, their inadvertent occurrence in foods or feeds remains an important economic consideration, even when the health and environmental risks are low. Various production options may be utilized to account for uncertainties in order to mitigate the risks of PMPs.