From the perspective of innovation, Industry 4.0 demands radical transformations of the manufacturing system, also referred to as manufacturing innovation. Despite extensive interest from industry, the translation of the visionary concept of Industry 4.0 into operational solutions remains challenging posing new requirements for how to approach manufacturing innovation, among others due to the increasing complexity and lack of transparency in the process. To support the adoption of Industry 4.0, this dissertation aims to establish a systemic approach to manufacturing innovation for Industry 4.0 encompassing both technical and human aspects of the transformation. Drawing on empirical research from an extensive amount of data collected from multiple Danish manufacturing companies, the study employs qualitative methods to explore and refine the understanding of manufacturing innovation for Industry 4.0 focusing on the innovation approach. The results of the dissertation evolve in three parts. The first part of the findings explores why the adoption of Industry 4.0 in industry is at a standstill. In the second part, characteristics of successful approaches to manufacturing innovation for Industry 4.0 are presented along with a process model for the adoption of Industry 4.0. In the last part of the findings, the research delves into the ‘sandbox’ approach as a tool for manufacturing innovation. The research offers essential knowledge necessary to advance industry practice to enhance the quality of the approach to manufacturing innovation in manufacturing companies, and thereby creates a strategic foundation for manufacturing. From a scientific perspective, the research contributes to establishing manufacturing innovation as a dedicated research area.