The Milan Cathedral, built between 1386 and 1813, is one of the largest masonry monuments ever built. After a brief description of the Cathedral, the paper presents the conceptual design of the monitoring system aimed at assisting the condition-based structural maintenance of the historic building. To the authors’ knowledge, the presented monitoring system is the largest ever implemented in a Cultural Heritage monument; in addition, appropriate strategies of Structural Health Monitoring have been developed for the continuous interrogation of sensors installed in the structure and the extraction from measured data of features which are representative of the current state of structural health.