Transforming Europe into a climate neutral economy and society by 2050 requires extraordinary efforts and the mobilisation of all sectors and economic actors, coupled with all the creative and brain power one can imagine. Each sector has to fundamentally rethink the way it operates to ensure it can be transformed towards this new net-zero paradigm, without jeopardising other environmental and societal objectives, both within the EU and globally. Given the scale of the transformation ahead, our ability to meet climate neutrality targets directly depends on our ability to innovate. In this context Research & Innovation programmes have a key role to play and it is crucial to ensure they are fit for purpose and well equipped to support the next wave of breakthrough innovations that will be required to achieve climate neutrality in the EU and globally by 2050. The objective of this study is to contribute to these strategic planning discussions by not only identifying high-risk and high-impact climate mitigation solutions, but most importantly look beyond individual solutions and consider how systemic interactions of climate change mitigation approaches can be integrated in the development of R&I agendas.