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Neglected and underutilized species (NUS) are referred to as species with under-exploited potentials with regard to food and nutrition security, health, income generation and environmental services. In the past, most breeding activities have concentrated on major crops, leading to overdependence on a few plant species of worldwide economic importance. The reasons for NUS being underutilized are complex and entail economic and agro-ecological constraints as well as lack of knowledge, awareness and supportive policies. Contextualization, decentralization and collaboration are proposed as important design principles for breeding strategies focusing on NUS. Four case studies illustrate how they are practically implemented in breeding programs. Two case studies focus on improving NUS for adaptation to climate variability and change: participatory breeding programs for sorghum and pearl millet in West Africa and Andean potatoes in Peru are taken as examples. Further case studies concentrate on improving agronomic and nutritional properties of local quinoa and amaranth varieties in Peru, and sensory quality of a less common vegetable crop in Germany. We discuss breeding strategies for NUS based on their objectives, the genetic resources used, breeding processes and techniques, as well as links to value chain development and seed systems. We conclude that breeding strategies for NUS should increasingly be embedded in multi-stakeholder strategies for collaborative learning and to expand the focus of interest from enhancing varieties towards building innovative institutions and partnerships that help develop sustainable food and farming systems and are linked to human needs.