How the growing world population can feed itself is a crucial, multi-dimensional problem that goes beyond sustainable development. Crop production will be affected by many changes in its climatic, agronomic, economic, and societal contexts. Therefore, breeders are challenged to produce cultivars that strengthen both ecological and societal resilience by striving for six international sustainability targets: food security, safety and quality; food and seed sovereignty; social justice; agrobiodiversity; ecosystem services; and climate robustness. Against this background, we review the state of the art in plant breeding by distinguishing four paradigmatic orientations that currently co-exist: community-based breeding, ecosystem-based breeding, trait-based breeding, and corporate-based breeding, analyzing differences among these orientations. Our main findings are: (1) all four orientations have significant value but none alone will achieve all six sustainability targets; (2) therefore, an overarching approach is needed: “systems-based breeding,” an orientation with the potential to synergize the strengths of the ways of thinking in the current paradigmatic orientations; (3) achieving that requires specific knowledge development and integration, a multitude of suitable breeding strategies and tools, and entrepreneurship, but also a change in attitude based on corporate responsibility, circular economy and true-cost accounting, and fair and green policies. We conclude that systems-based breeding can create strong interactions between all system components. While seeds are part of the common good and the basis of agrobiodiversity, a diversity in breeding approaches, based on different entrepreneurial approaches, can also be considered part of the required agrobiodiversity. To enable systems-based breeding to play a major role in creating sustainable agriculture, a shared sense of urgency is needed to realize the required changes in breeding approaches, institutions, regulations and protocols. Based on this concept of systems-based breeding, there are opportunities for breeders to play an active role in the development of an ecologically and societally resilient, sustainable agriculture.