Autonomy is a concept constantly referred to in Latin American foreign policy analysis, especially with respect to Argentina and Brazil. As great powers continue to exert effective control over peripheral economies and their political decision making, autonomy emerges as a possibility for self-determination in the areas where hegemonic powers’ economic, political, and cultural interferences are expressed. Although this is not a new concept, the quest for autonomy within the “global periphery”—and elsewhere too—still remains relevant. Helio Jaguaribe and Juan Carlos Puig’s theoretical approaches are fundamental epistemological contributions to international relations (IR), not only in South America (where the theoretical approach was first developed) but also to the wider IR field outside the mainstream scholarship. In line with global historical changes, autonomy took on some subsequent new meanings, which led to new and heterogeneous formulations that transformed, and in certain cases also contradicted, the very genesis of the idea of autonomy. As a result, the so-called autonomy “with adjectives” emerged within IR peripheral debates. The 21st century witnessed the rebirth of the concept amid the rise of multilateralism and the new Latin American regionalism, which brought its relational character to the fore. Some of the new approaches to autonomy, especially from Brazil, used the concept as a methodological tool to understand the historical evolution of the country’s foreign policy. As such, autonomy and its theoretical reflection remain central to the analyses and interpretations of the international relations of peripheral countries, and it is in this sense that the autonomy can be highlighted broadly as a Latin American contribution to IR discipline. The concept of autonomy has a unique and foundational content referred to the discussion of the asymmetries in the global order. Studying autonomy is critical to understanding peripheral countries’ problems and dynamics.