Globally, the use of untreated, often diluted, or partly treated wastewater in agriculture covers about 30 million ha, far exceeding the area under the planned use of well-treated (reclaimed) wastewater which has been estimated in this paper at around 1.0 million ha. This gap has likely increased over the last decade despite significant investments in treatment capacities, due to the even larger increases in population, water consumption, and wastewater generation. To minimize the human health risks from unsafe wastewater irrigation, the WHO’s related 2006 guidelines suggest a broader concept than the previous (1989) edition by emphasizing, especially for low-income countries, the importance of risk-reducing practices from ‘farm to fork’. This shift from relying on technical solutions to facilitating and monitoring human behaviour change is, however, challenging. Another challenge concerns local capacities for quantitative risk assessment and the determination of a risk reduction target. Being aware of these challenges, the WHO has invested in a sanitation safety planning manual which has helped to operationalize the rather academic 2006 guidelines, but without addressing key questions, e.g., on how to trigger, support, and sustain the expected behaviour change, as training alone is unlikely to increase the adoption of health-related practices. This review summarizes the perceived challenges and suggests several considerations for further editions or national adaptations of the WHO guidelines.