This paper synthesizes the lessons learned and challenges encountered when applying Indigenous and non-Indigenous knowledge and methods in natural and cultural resource management (NCRM) in northern and central Australia. We primarily draw on the papers within this special issue of Ecological Management & Restoration, which originated largely from the Indigenous land management symposium at the 2010 Ecological Society of Australia conference. Many of the papers and therefore this article discuss practical experiences that offer insight for enhanced on-ground cross-cultural NCRM and can inform broader thinking and theoretical critiques. A wider literature is also drawn upon to substantiate the points and broaden the scope of the synthesis. Four key themes for consideration in collaborative cross-cultural NCRM are discussed. They are as follows: 1. The differences in environmental philosophy between Indigenous and non-Indigenous cultures profoundly shape perceptions of environmental management; 2. Cross-cultural awareness of Indigenous and non-Indigenous knowledge and methods; 3. The mechanics of two-way approaches to ecological research and managing country (NCRM as perceived by Indigenous people) and 4. Operational challenges for Indigenous NCRM organizations. To conclude, we point out five broad principles for managing country using Indigenous and non-Indigenous knowledge: (i) Recognise the validity of both Indigenous and non-Indigenous environmental philosophies; (ii) Create more opportunities for improved cross-cultural understanding, respect, and collaborations; (iii) Involve Indigenous people and their knowledge and interests at all stages of the Indigenous NCRM project or research (including planning, design, implementation, communication, and evaluation); (iv) Ensure that time and continuity of effort and resources are available (to undertake participatory processes and for trust-building and innovation) and (v) Establish high-level political support through legal and policy frameworks to maintain continuity of government commitment to Indigenous NCRM.