National suicide prevention programmes that have been successful in reducing rates or keeping them low have been intentional, with collective alignment of local, regional and national priorities. Prevention efforts must begin well before individuals become suicidal, complementing readily available clinical services that address the needs of acutely distressed persons. These efforts, which focus on the antecedent risks and vulnerabilities of key populations, have the potential to diminish premature mortality from multiple causes, even as reducing suicide is the outcome of primary interest. In this commentary, I consider four key challenges that must be confronted in order to develop effective, broadly reaching systemic strategies that, at once, can be adapted locally while being implemented nationally – challenges that are framed in a social–ecological context. They involve defining the scope of the problem, meeting essential data needs, developing and modelling measurable implementation strategies and building prevention efforts based on shared culture and values.