<p>Genome-wide screening can be offered at various stages of life and serve multiple purposes, including early detection of treatable conditions, achieving health benefits, or enhancing reproductive choices. Although genome-wide screening offers many new possibilities, determining which genomic data to analyse, how to interpret results, and how to communicate findings, presents significant challenges. In our research, we explored considerations for responsible genome-wide screening by combining a normative analysis of three different settings (population screening, opportunistic screening, and direct-to-consumer genetic testing) with an exploration of stakeholder views (among 25 professionals and 15 potential users of screening). In doing so, we focused on the proportionality criterion and four key screening issues: (1) dealing with unsolicited, secondary and uncertain findings; (2) information and consent; (3) privacy, storage, and (re)use of data; and (4) non-participation in screening. Our findings show broad consensus on the need for a cautious approach towards genome-wide screening. The proportionality criterion requires that benefits outweigh harm on both individual and societal level. Although genome-wide testing offers a range of possible expansions of screening, evidence for the proportionality of an expansion is not always available. The expansion of direct-to-consumer genetic testing raises the most concerns in terms of proportionality. In all screening settings, the position of and advocacy for newborns and children deserve special attention. Given the already scarce resources and personnel in healthcare, responsible implementation of genome-wide screening must be grounded in well-defined normative frameworks, supported by pilot studies that critically evaluate harms and benefits on both individual and societal level.</p>