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Water resources systems analysis (WRSA) combines quantitative and qualitative methods informed by multiple scientific disciplines, serving many broad water-related societal goals such as providing safe drinking water and mitigating floods and other disasters. Water utilities, flood control districts, and government agencies have regulatory mandates to meet these objectives. However, these entities face growing challenges including trade-offs between human and ecological needs, climate change, increasing population, aging infrastructure, and pressures from interconnected sectors such as food and energy. The aim of WRSA research, then, is to contribute new general methodologies for addressing these challenges and specific solutions for pressing problems. However, it is not always clear that knowledge developed in the WRSA field is generalizable (across case studies and regulatory contexts) and actionable (both in real-world systems and across academic fields). This presentation argues the need for systematic guiding questions for WRSA research. Such questions should address the relative importance of normative and positive analysis, the proper formulation of optimization problems, and the fidelity of mathematical representations of water resources systems. After exploring these ideas, we suggest pillars of guiding research questions for the field to support the aim of increasing generalizable and actionable knowledge within WRSA and improved water system sustainability.