Overall, the deregulation of genetically engineered (GE) crops for commercial cultivation in North America has been a success story. In several cases, however, GE crops have sparked concerns and disagreements among the stakeholders and there are incidences of court lawsuits, including a recent one on glyphosate resistant (GR) alfalfa (Medicago sativa, L.). While GE crops can provide operational benefits to farmers, challenges are looming from commercialization of perennial GE crops. The unique ecology and biology of these crops and GE alfalfa in particular can facilitate adventitious presence (AP) of GE traits and it makes more visible that economic risks for conventional growers and food/feed producers have not been adequately addressed by the GE regulatory system in the United States (US). Asynchronous market approvals and the existence of a number of GE sensitive export markets create uncertainties among the exporters. Policy development in these fields may be helpful for ensuring a broader acceptance and market success of GE agriculture in general. The analysis is focusing on the US, although many diagnosed problems are also relevant to other jurisdictions—in particular if no co-existence policy is in place.