In this chapter, the authors engage with the widespread and influential approach of national innovation systems (NISs). They discuss its adequacy to non-OECD (Organisation for Economic Co-operation and Development) countries, especially in Latin America, where it is abundantly implemented and tends to be reified, which leads to a situation where relevant contextual elements tend to be ignored. Although the NISs approach is meant to address the most pressing needs of the economies it applies to, namely solving poverty, reducing social inequalities, increasing productivity and creating jobs, the authors argue that it would benefit from developing a more encompassing scope, allowing integration of greater diversity and complexity. By retracing the history of regimes of science, technology and innovation (STI) in Latin America, the authors explore the problems faced by actors willing to use NISs more reflexively. They hereby discuss the effectiveness of STI policies in non-OECD countries. Finally, they formulate a research agenda with three suggestions for further engaging NISs both conceptually and practically. Using such analytical perspectives, they argue, might benefit scholarly work about NISs and could also allow for a better articulation with STI regimes in Southern countries.