How can we better tackle sustainability issues such as reducing carbon emissions and achieving sustainable development goals such as reducing poverty? To address this question, the talk will highlight some research agenda from a System-of-Systems (SoS) perspective. SoS provides an alternative framework for structuring and analyzing a problem and designing effective policy and intervention solutions. Three illustrative case studies will be presented. First is the socio-environmental impacts of lithium mining. Increased demand for lithium-ion batteries to power clean technologies such as electric-drive vehicles can cause a degradation of water resources, biodiversity, and societal well-being where the minerals are extracted. Second is interventions for conserving food, energy, and water resources at the household level. This poses a significant challenge due to the complex interplay between human behaviors, technologies, and policies. In an NSF-funded research project, a role-playing game has been developed to increase awareness for environmental issues and influence behaviors towards more sustainable practices. Third is the implementation of the UN sustainable development goals (SDGs). The adoption of the SDGs presents an opportunity to steer the global development efforts to sustainable pathways. However, it also poses a challenge as to how to operationalize and achieve the various goals in cost-effective, inclusive, and equitable ways. The goal of the talk is to stimulate a discussion on the potential and challenges in advancing the SoS methodology.