Community-based research, that is, the meaningful involvement of affected populations in the production of scientific knowledge that concerns them, is a political struggle and an ethical necessity. Coalition PLUS, an international network of organizations (most of them NGOs) fighting against HIV and hepatitis, created a community-based research laboratory (CBRL) composed of people from more than sixteen countries and various disciplinary fields. The objectives of the CBLR are to build research capacity, ensure collaboration with local and international academic research centers, and develop international research projects. The CBRL acts as a bridge between different partners, reconciling sometimes divergent interests, and must provide mediation and support to promote dialogue, transparency, and a relationship of trust between the communities and academic researchers. However, the need for scientific legitimacy obliges us to continuously seek a balance between responding to the needs of the field and using rigorous scientific methods, while optimizing and prioritizing existing resources. The permanent quest for this balance has led the CBRL to reorganize its mode of operation to optimize existing synergies with academic research laboratories, with a view to asserting its scientific legitimacy and continuing to contribute to social transformation through community-based research that is both innovative and of high quality. This paper provides a critical reflection on the issues, challenges, practices, and solutions of community-based research within the Coalition PLUS network.