At-risk users are people who experience risk factors that augment or amplify their chances of being digitally attacked and/or suffering disproportionate harms. In this systematization work, we present a framework for reasoning about at-risk users based on a wide-ranging meta-analysis of 95 papers. Across the varied populations that we examined (e.g., children, activists, people with disabilities), we identified 10 unifying contextual risk factors — such as marginalization and access to a sensitive resource — that augment or amplify digital-safety risks and their resulting harms. We also identified technical and non-technical practices that at-risk users adopt to attempt to protect themselves from digital-safety risks. We use this framework to discuss barriers that limit at-risk users’ ability or willingness to take protective actions. We believe that researchers and technology creators can use our framework to identify and shape research investments to benefit at-risk users, and to guide technology design to better support at-risk users.