This policy brief outlines a human rights-based approach to the design and implementation of the multilateral mechanism and Cali Fund for benefit-sharing from the use of digital sequence information on genetic resources. Drawing on research conducted in Indigenous, Afro-descendant, and farming territories in Colombia, it highlights the urgent need for a fair and inclusive benefit-sharing system that recognizes the rights and contributions of Indigenous people and local communities (IP&LCs). This brief outlines critical recommendations for decision-making and advocacy in the wake of the 2024 United Nations Biodiversity Conference in an effort to ensure fair compensation and reciprocity for IP&LCs while addressing structural inequalities.