The introduction of herbicide-tolerant (HT) genetically engineered (GE) soybeans has raised new challenges for the European risk assessment of imported food and feed. Food and feed products derived from these plants may show specific patterns of chemical residues and altered nutritional composition. Furthermore, there has been a substantial increase in the usage of herbicides in soybean production due to the emergence of resistant weeds. This concerns particular glyphosate-based herbicides and also other herbicides. In this review, we give an overview of available data regarding glyphosate application on HT GE soybeans in North and South America. We have further compared this data with herbicide applications in experimental field trials conducted by the industry. We conclude that field trials carried out for risk assessment purposes do not generally represent the real agronomic conditions in commercial HT GE plant cultivation. In most cases, neither the applied dose nor the number of applications match real conditions. This finding is especially relevant for risk assessment since a review of relevant publications shows that the amount and timing of spraying glyphosate as a complementary herbicide onto HT GE plants can impact their composition; this is relevant to EFSA comparative risk assessment of GMOs. Further, closely related issues were identified that overlap with EU GMO and pesticide regulation, but are not currently considered. These issues concern indirect, cumulative and combinatorial effects as well as the assessment of mixed toxicity. Consequently, current risk assessment practice for HT GE plants cannot be considered to fulfil EU regulatory standards which require the safety of food and feed to be demonstrated. It is much more likely that concerns about the health risks of HT GE plant material used for food and feed have been underestimated. We therefore conclude that the EU risk assessment of food and feed derived from HT GE plants needs substantial improvement.