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The rise of knowledge-based territorial development has been fuelled primarily by aspirations of competitiveness and wealth creation. Another upcoming ambition is that of sustainability, not only as an accompanying goal but as a core mission driving territorial initiatives such as clusters development. This paper explores mission-driven territorial development along theoretical and empirical lines. The paper starts by discussing a basic heuristic model intersecting the three concepts of ‘mission’, ‘knowledge’ (distinguishing ‘substantive’ and ‘significant’ knowledge) and ‘governance’. This leads to an analytical framework for territorial development focusing on (1) mission formulation, (2) production and exchange of knowledge in supportive milieus, (3) embedding of substantive knowledge, (4) anchoring of significant knowledge, and (5) feeding of significant knowledge into the (re) design of institutions and strategies of policy design and implementation. This framework is applied to three cases of ‘Metropolitan Food Clusters’ to illustrate and test the framework. The paper shows how especially the continuous anchoring of significant knowledge poses major challenges to knowledge-based territorial development and should be a central issue in future research and policy. [ABSTRACT FROM AUTHOR]