In recent years the framings of global health security have shifted while the structures governing global health have largely remained the same. One feature of the emerging re-ordering is the unresolved allocation of accountability between state and non-state actors. This brings to critical challenges to global health security to the fore. The first is that the consensus on the seeming shift from state to human security framing with regard to the global human right to health (security) risks losing its salience. Second, this conceptual challenge is mirrored on the operational level: if states and non-state actors do not assume responsibility for health security, who or what can guarantee health security? In order to address global health security against the backdrop of these twenty-first Century challenges, this article proceeds in three parts. First, it analyses the shortcomings of the current state-based World Health Organization (WHO) definition of health security. Second, taking into account the rising pressures posed to global health security and the inadequacy both of state-based and of ad hoc non-state responses, it proposes a new framing. Third, the article offers initial insights into the operational application of beyond state responses to (health) security challenges.