This Distinguished Lecture discusses the role of digital avionics and Air Traffic Management (ATM) systems research in enabling the safe, efficient and sustainable development of the air and space transport sector. The aim is to disseminate recent technological/regulatory advances and to identify opportunities for industrial innovation in strategic areas, such as future Decision Support Systems (DSS) for Intent Based Operations (IBO) and Multi-Domain Traffic Management (MDTM). Starting from SESAR/NextGen top-level requirements, this paper presents integrated Communication, Navigation and Surveillance/ATM and Avionics (CNS+A) system architectures implementing 4-Dimensional Trajectory Optimisation (4DTO) algorithms, data link communications and enhanced surveillance technologies, as well as adaptive cognitive forms of Human-Machine Interface and Interaction (HMI2), allowing the automated negotiation and validation of aircraft intents for safer and more efficient ATM operations. As an integral part of this CNS+A evolutionary process, specific requirements for Unmanned Aircraft Systems (UAS) navigation, communication and cooperative/non-cooperative Sense-and-Avoid (SAA) are being addressed in order to allow the safe and unrestricted access of UAS to all classes of airspace. In parallel with air transport developments, progress in spaceflight research has led to the introduction of various manned and unmanned reusable space vehicle concepts, opening up uncharted opportunities for the newborn space transport industry. For future space transport operations to be technically and commercially viable, it is critical that an acceptable level of safety is provided, requiring the development of novel digital tools (e.g., mission planning and decision support systems) that utilize advanced CNS+A technologies, and allowing a seamless integration of space operations in the current ATM network. While the technical maturity of propulsive and vehicle technologies is relatively high, a recent review of emerging platform operational concepts highlights the challenges (and opportunities) brought in by the adoption of cyber-physical and autonomous systems for integration of point-to-point suborbital spaceflight with conventional atmospheric air transport. In particular, various viable launch and re-entry methodologies were addressed, where the physical and computational limitations of these approaches was identified and applicability to future commercial space transport operations was assessed. Recent research is turning greater attention to the on-orbit phase, where the unique hazards of the space environment are being examined and the necessary elements required for space object de-confliction and collision avoidance modelling are analysed. The evolution of regulatory frameworks supporting spacecraft operations is a conspicuous factor, which requires a holistic approach and extensive government support for the successful development and establishment of sustainable business models, including space debris mitigation strategies, operational risk assessment and liability issues. Within the atmospheric domain, extensions and alternatives to the conventional airspace segregation approaches must be identified including ATM/ATFM techniques to facilitate the integration of new-entrant platforms. Lastly, adequate modelling approaches to meet on-orbit risk criteria must be developed and evolutionary requirements to improve current operational procedures (and associated regulatory frameworks) must be introduced.