The number of health systems strengthening (HSS) programs has increased in the last decade. However, a limited number of studies providing robust evidence for the value and impact of these programs are available. This study aims to identify knowledge gaps and challenges that impede rigorous monitoring and evaluation (M&E) of HSS, and to ascertain the extent to which these efforts are informed by existing technical guidance. Interviews were conducted with HSS advisors at United States Agency for International Development‐funded missions as well as senior M&E advisors at implementing partner and multilateral organizations. Findings showed that mission staff do not use existing technical resources, either because they do not know about them or do not find them useful. Barriers to rigorous M&E included a lack suitable of indicators, data limitations, difficulty in demonstrating an impact on health, and insufficient funding and resources. Consensus and collaboration between international health partners and local governments may mitigate these challenges. Copyright © 2016 John Wiley & Sons, Ltd.