Building reuse is a strategy for built heritage enhancement. The establishment of new activities in an existing building can have positive effects on the urban and territorial context and modify the dynamics of socio-economic development. If the reuse is considered as a cultural development strategy and not limited to a single building but to both buildings and infrastructures, these effects are amplified. This is the case of railway heritage, affected by an increasingly vast process of abandonment. The Italian policies for encouraging road transport and the communication models of the digital era have contributed to the gradual desertion of railway lines. This requires effective reuse models, to avoid that the Ferrovie dello Stato (State Railways) continue to carry the heavy burden of managing assets no longer able to generate income. The analysis of numerous station reuse cases, at an international level, lead to the selection of the case of the Postal Museum and Mail Ride in London as an example of good practice. The proposed methodology identifies a set of evaluation criteria and indicators to assess the effectiveness of adaptive reuse projects both in terms of their ability to protect built heritage identity and to modify the orientation of the territorial context’s development towards socio-economic sustainability guidelines.