About 20 years after the market introduction of the first GM plants, we review whether or not uncontrolled spread occurred. We summarise cases documented in the scientific literature and derive conclusions for the regulation of the authorisation of new events. Several cases documented in North and Central America and Japan show that transgenes have spread beyond cultivation areas. Important examples are bentgrass (Agrostis stolonifera), oilseed rape (Brassica napus) and cotton (Gossypium hirsutum). Several factors can be identified as relevant for transgene dispersal in the environment. Grasses (Poaceae), in particular, show a high potential for persistence and invasiveness, and wild relatives that can cross with the crop plants are a major factor in the unintended spread of the transgenes. There are significant uncertainties in predicting which transgenes will escape and how they will interact with the environment. For example, climate change is likely to have a major impact on the invasive potential of some plant species. The uncontrolled spread of transgenes is therefore a remaining challenge for regulators. We discuss some of these issues in the context of EU regulations since these regulations explicitly refer to the precautionary principle in the assessment of uncertainties. We found the that the precautionary principle as established in EU Directive 2001/18 can only be applied where efficient measures are available to remove genetically engineered organisms from the environment should this become necessary. If a removal from the environment would not be practically feasible, undesirable developments could not be mitigated.