In the domain of Human Computer Interaction (HCI), recent advances in sensors, communication technologies, miniaturization and computing capabilities have led to new and advanced forms of interaction. Among them, Mixed Interactive Systems (MIS), form a class of interactive systems that comprises augmented reality, tangible interfaces and ambient computing; MIS aim to take advantage of physical and digital worlds to promote a more transparent integration of interactive systems with the user's environment. Due to the constant change of technologies and the multiplicity of these interaction forms, specific development approaches have been developed. As a result, numerous taxonomies, frameworks, API and models have emerged, each one covering a specific and limited aspect of the development of MIS. To support a coherent use of these multiple development resources and contribute to the increasing popularity of MIS, we have developed a framework based on Model-Driven Engineering. The goal is to take advantage of Model-Driven Engineering (MDE) standards, methodology and tools to support the manipulation of complementary Domain Specific Languages (DSL), to organize and link the use of different design and implementation resources, and to ensure a rationalized implementation based on design choices. In this paper, we first summarize existing uses of MDE in HCI before focusing on five major benefits MDE can provide in a MIS development context. We then detail which MDE tools and resources support these benefits and thus form the pillars of the success of an MDE-based MIS development approach. Based on this analysis, we introduce our framework, called Guide-Me, and illustrate its use through a case study. This framework includes two design models. Model transformations are also included to link one model to another; as a result the frameworks coverage extends from the earliest design step to a software component-based prototyping platform. A toolset based on Eclipse Modeling Framework (EMF) that supports the use of the framework is also presented. We finally assess our MDE-based development process for MIS based on the five major MDE benefits for MIS.