Fonio is the smallest of the millets and one of the world’s oldest crops, grown across West Africa. Some landraces are the world’s fastest maturing cereals, helping small-scale farmers in semi-arid regions survive mid-season hunger as they await harvesting of primary crops. Fonio comprises two species distinguished by spikelet colour (white and black), with white fonio being dominant. Here we review research in white fonio from a cross-disciplinary, systems-based perspective, including germplasm conservation, crop breeding, agronomy, mechanization, and value chain development. Fonio is consumed like rice and comparable or superior nutritionally, but can survive dry/marginal soils. Despite food security potential, it remains semi-domesticated and underutilized, associated with low yield, lodging, seed shattering and post-harvest drudgery. Recently, there have been exciting advances in white fonio germplasm collection, genome sequencing, population structure analysis and agronomic/stakeholder surveys. Controlled experiments have identified physio-morphological-metabolomic acclimation traits as targets to breed fonio for improved drought tolerance, critical in the Sahel region of Western Africa, which is dry and among the most vulnerable to climate change and food insecurity. These advances have laid the foundation to develop fonio as an economically viable crop to improve the livelihoods of Sahelian indigenous peoples. White fonio could serve as a model for how modern techniques can be used to fully domesticate ancient crops and adapt them to climate change.