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Innovation in small and medium-sized enterprises (SMEs) is one of the main objectives set in the Lisbon agenda. In this paper, a large-scale intervention program is reflected upon that aimed for the enhancement of innovation in 650 SMEs in the Euregion Meuse-Rhine. In particular, four lessons are drawn concerning the design and implementation of robust regional innovation policy. Sustainability is a goal that can be reached when innovation stimuli lead to continuous social and economic changes when all the change agents invest in an automatic reflex to assess and match their activities with the specific demands in the dynamic environment.