Animal-based research not only evokes ethical questions on a theoretical level, as discussed in the previous chapters, but also calls for an ethical assessment within a legal framework. In this chapter the main elements of the ethical review systems in North America and Europe are described and discussed. The focus lies on the core task of these Animal Ethics Committees, i.e., ensuring the principle of 3Rs are applied in the suggested research protocols and the performance of a Harm-Benefit Analysis, including, e.g., welfare assessment and research quality, while elaborating on current literature in the field and issues arising due to use of genetically modified animals. Further, challenges in the review system in terms of defining the role of committee members, and ensuring transparency and societal trust are highlighted.