Today, the variety of complex products, low volume and decreasing life cycles require a combination of multiple skills that, often, do not exist in a single organization. This raises the need to extend the traditional organization towards the extended virtual enterprise. During the last decade several research projects developed concepts, methods and tools to support the design and operation of the virtual enterprises. However, the impact in industry remains low mainly due to the lack of vertical and horizontal integration, both at business and technical level. Industry 4.0 may be the missing enabler for effective virtual enterprises, once it integrates both business entities and technical entities into a single concept - the Industry 4.0 component – thus enabling enhanced interoperability. This paper presents innovative Industry 4.0 approaches, concepts, methods and tools applied to real manufacturing environments, showing how they enable the creation of cyber-physical production systems leading to a flexible, efficient and seamlessly virtual enterprise.