This chapter analyses how neglected and underutilized crops (NUCs) have the potential to convert food systems to a changing climate, ecological, and nutrition environment. The study is motivated by the fact that the global agricultural sector has continued to be vulnerable because of overdependence on few staple crops that has contributed to environmental degradation, food staleness and increased risks of production with the advent of climate change. The chapter is based on a mixed-method approach to qualitative analysis and involves research synthesizing over 120 peer-reviewed articles, 32 cases of countries and 15 global policies to evaluate the adaptability nature evidences, socioeconomic advantages, and obstacles of NUCs scales up. The evaluation indicates that solutions such as NUCs have the potential to enhance the resilience of smallholders (25–40%) due to enhanced drought and heat tolerance, and low soil fertility, adding dietary diversity (30–60% greater vitamin and nutrient content than primary staples). The case studies in Africa, Asia and Latin America demonstrate yield stability gains of 20–35% when the case was under stress and incomes enhanced by 10–28% when the value chains were established. Nevertheless, its use remains not popular due to systemic barriers, such as poor seed systems, lack of research funding (a small part, 3–5% of crop research), and lack of brand awareness. The chapter finds that mainstreaming NUCs would need a concerted effort to address research, policy, and markets, and identifies genomics-assisted breeding, integration of climate-smarter agriculture, public–private collaboration and facilitating the global structure both through Food and Agriculture Organization (FAO), International Fund for Agricultural Development (IFAD), Consultative Group on International Agricultural Research (CGIAR), and the UN Food Systems Summit as priorities. The efforts to reinforce these pathways will prove highly beneficial in achieving Sustainable Development Goal (SDG) 2 by 2030, zero hunger due to the effective and healthy food systems.