The Tri-National Dja - Odzala - Minkebe Forest landscape (TRIDOM) covers 178000 km2 across the borders of Cameroon, Gabon and the Republic of Congo. Almost 97% is covered by sparsely populated lowland tropical rainforest and is globally important for the conservation of large mammals (elephants, gorillas, chimpanzees). It is also an emerging iron ore province with several deposits currently being explored and two mining projects ready for exploitation. Encouraging investment while respecting the legal and customary rights of local populations and conserving biodiversity represents a major challenge. Conservationists fear that the needed infrastructure (railroads, roads, transmission lines, hydropower dams) and the associated impacts (especially from the influx of population) will lead to the fragmentation of TRIDOM. It risks being reduced to a mosaic of vulnerable, isolated protected areas, no longer fit to conserve its mega-fauna or maintain large scale ecosystem processes, but developing mining projects with a no-net loss (NNL) or even a net gain (NG) biodiversity objective as a condition for access to finance raises considerable technical and institutional challenges. A landscape-level approach is needed to take into account and mitigate indirect and cumulative impacts. Land-use rights are granted through sector-specific concessions that have varying requirements in terms of biodiversity and rural livelihoods. Elaborating long-term arrangements for implementing and financing biodiversity offsets will thus require close collaboration between financial institutions, mining companies, conservation NGOs and government bodies from different sectors. We investigate the opportunities and obstacles for achieving NNL/NG objectives in the TRIDOM and draw lessons for other biodiversity-rich landscapes faced with the perspective of large-scale environmental and socio-economic changes.