The Upper Bermejo River Basin (UBRB) is the most bio-diverse region in Argentina. A rugged territory and a long history of human settlement, combined with social and political isolation, have resulted in large areas with well-preserved forests, a large number of wild plant and animal species, and indigenous crops. Several factors, including agriculture expansion, intense logging activities, and oil and gas prospecting, are posing a threat to biodiversity. Current national parks and reserves are not enough to secure the survival of functional populations, especially of the large mammals. Conservation of biodiversity in the UBRB requires a broader approach: e.g. protection of the most sensitive areas outside present reserves; maintaining the remaining forest matrix under sustainable management regimes, involving the local communities in the process; and encouraging uses synergetic with conservation. Recent purchases by private enterprises of new protected areas, the willingness of local administrations to establish a new legal conservation framework, and local communities considering sustainable management of their lands, represent encouraging opportunities for the region.