The Nagoya Protocol on access to genetic resources and the fair and equitable sharing of benefits arising from their utilization could help conserve genetic diversity, bridge the technological gap between the North and the South, and compensate indigenous and local communities for the use of their traditional knowledge associated to the utilization of biodiversity. However, as the text of the agreement appears complex, ambiguous and controversial, serious national implementation challenges emerge. This research outlines three of them: (1) a complex, dynamic and disputed material scope; (2) doubts on Nagoya´s degree of retroactivity and (3) problems in relation to the selection and operationalization of the envisaged compliance measures. After discussing each of the challenges, valuable insights and possible solutions are offered in order to facilitate the national implementation of the Protocol.