This paper proposes a novel framework for the development of interventions in vulnerable populations. The framework combines a complex systems lens with syndemic theory. Whereas funding bodies, research organizations and reporting guidelines tend to encourage intervention research that (i) focuses on singular and predefined health outcomes, (ii) searches for generalizable cause-effect relationships, and (iii) aims to identify universally effective interventions, the paper suggests that a different direction is needed for addressing health inequities: We need to (i) start with exploratory analysis of population-level data, and (ii) invest in contextualized in-depth knowledge of the complex dynamics that produce health inequities in specific populations and settings, while we (iii) work with stakeholders at multiple levels to create change within systems.