In this letter, we reflect on recent modifications of the regional innovation system (RIS) approach that have been prompted by persistent environmental, social, and economic problems. Scholars have begun to advocate a reorientation of the RIS framework towards addressing territorial sustainability challenges and have introduced the notion of challenge-oriented regional innovation systems (CORIS). While the CORIS approach holds promise given the challenges of our time, several unresolved issues remain. We elaborate on and discuss three themes that demand further research. Firstly, there is a need for in-depth studies of the geographies of problems. Systematic analyses of the origins and interrelations of territorial challenges are high in demand. Secondly, the geographies of challenge-oriented innovation-exnovation dynamics warrant more attention. We argue that future research should delve into questions around the development, testing and upscaling of innovative solutions, as well as the unlocking and destabilisation of unsustainable practices in various spatial contexts. Lastly, we contend that a better understanding of the geographies of RIS reconfiguration is necessary. This entails shedding light on various forms of system-level agency involved in reorienting or transforming historically-grown real-world RIS in different types of regions.