Urgency and political incentives towards grand challenges, such as anthropogenic climate change, increase the importance of multi-actor and cross-sectoral cooperation approaches. One such approach referred to as mission-oriented innovation (MOI) encompasses multi-actor and cross-sectoral cooperation towards tackling grand challenges. However, there is a significant research gap regarding the engagement of SMEs in MOI. The ability to innovate and adapt makes SME engagement pivotal. This study aims to examine barriers towards SME engagement in MOI. Barriers were uncovered through an inductive qualitative case study. By performing a thematic analysis, barriers regarding lack of communication, resource distribution, and differences between political domains were uncovered. Contributing toward the significant gap in current literature, this study increases the knowledge towards engaging SMEs in MOI.