Persistent problems feature prominently in transition management and system innovation literature. They serve both as a point of departure, and as justification for the contention that a system innovation is needed. The concept 'persistent problem' however is underdeveloped; it is used to label (symptoms of) problems that appear to be complex, uncertain, difficult to manage, and difficult to grasp, but as such provides no way for unravelling how the persistence of these problems actually works. A better understanding can help new practices, like niche-innovations, to overcome enduring problems, contributing to a transition or system innovation. Drawing on the work of Giddens and others, this paper proposes a conceptualisation that can be used to identify and unravel persistent problems. The conceptual framework is built on the notion of systemic reproduction, and further operationalised by iteratively combining a historically informed system analysis with an actor-guided system analysis. The historically informed analysis focuses on features that are exactly the strongholds of the current system, but are said to have negative side effects. In concurrence with that, the systemic reproduction of these negative side effects can be unravelled by analysing how new practices shape their agency in relation to their direct environment. A persistent problem then is a systemically reproduced negative side effect of a success factor of the system in focus. The operationalisation brings the conceptual framework to the actor level, and opens up possibilities for investigating how systemically embedded problems manifest themselves in the daily practice of actors that try to take on enduring problems. In the second part of the paper, this approach is illustrated by using it to unravel problems of tenability of the Dutch health care system. A historically informed analysis is integrated with an analysis of a new practice in health care that deals with patients who suffer from medically unexplained physical symptoms. © 2012 Elsevier Inc..