This article introduces the concepts and ideas behind Industry 4.0 and discusses the role of simulation and simulation standards for implementing it. We argue that the success of Industry 4.0 highly depends on the success of interconnected cyber-physical systems (CPS) which can only be implemented with up-front simulation. This up-front simulation and development of CPS is often associated with the term of building the “digital twin” for the respective CPS. Digital twins are typically defined as digital representations which represent the real system and its current state in a digital model. For investigating their dynamic behavior, digital twins must have properties typically associated with simulation models. In this article, we discuss requirements and potential solutions for the successful implementation of digital twins as well as the implications that this has on simulation standards. As an example, digital twins as representations of a CPS will have the need to communicate with other digital twins; hence a modular approach for building federations of digital twins is needed. Beyond that, also a need for standardized communication between the digital twin and the real CPS arises. The article will therefore discuss currently available interoperability standards, like the High Level Architecture (HLA) on the simulation side, and Open Platform Communications (OPC) Unified Architecture (OPC UA) on the control hardware side and how well they match the requirements that Industry 4.0 with its CPSs and digital twins imposes. The article also includes our opinion on the need for the future evolvement of existing standards.