As eluded in previous studies, with special reference to those carried out in the European framework, some innovative high-speed aircraft configurations have now the potential to assure an economically viable high-speed aircraft fleet. They make use of unexploited flight routes in the stratosphere, offering a solution to the presently congested flight paths while ensuring a minimum environmental impact in terms of emitted noise and green-house gasses, particularly during stratospheric cruise. Only a dedicated multi-disciplinary integrated design approach could realize this, by considering airframe architectures embedding the propulsion systems as well as meticulously integrating crucial subsystems. In this context, starting from an in-depth investigation of the current status of the activities, the STRATOFLY project has been funded by the European Commission, under the framework of Horizon 2020 plan, with the aim of assessing the potential of this type of high-speed transport vehicle to reach Technology Readiness Level (TRL) 6 by 2035, with respect to key technological, societal and economical aspects. Main issues are related to thermal and structural integrity, low-emissions combined propulsion cycles, subsystems design and integration, including smart energy management, environmental aspects impacting climate change, noise emissions and social acceptance, and economic viability accounting for safety and human factors. This paper aims at summarizing the main challenges and goals of the STRATOFLY project, highlighting the steps forward with respect to the past European Projects and underlying the next planned goals.