Design Structure Matrices (DSMs) and Domain Mapping Matrices (DMMs) are generally used by designers for dynamic optimization of engineering design processes and products. Both methodologies help producing valuable results; however, they are lacking a holistic view onto the processes and products. Dependencies that span multiple product development domains can therefore not be recognized with isolated DSM or DMM analysis. In this paper, we present an integrative approach that combines DSMs and DMMs to obtain the Multiple Design Structure Matrix (MDSM). This methodology offers the possibility to analyze multiple product development domains using one coherent matrix representation form. A holistic perspective helps the designer to identify domain-spanning structures that would not have been recognized with single-domain optimization approaches or isolated analysis of the DSMs and DMMs. Domain-spanning structures are important to identify, as they may cause unpredictable product or process behavior. Our research showed that a holistic perspective can help designers to identify important elements more easily and therefore save time and enhance quality in analysis of engineering systems design. The framework we present consists of a proposal for the selection of appropriate product development domains, their integration, and the derivation of analysis results.