A hypercaloric diet combined with a sedentary lifestyle is a major risk factor for the development of insulin resistance, type 2 diabetes mellitus (T2DM) and associated comorbidities. Standard treatment for T2DM begins with lifestyle modification, and includes oral medications and insulin therapy to compensate for progressive β-cell failure. However, current pharmaceutical options for T2DM are limited in that they do not maintain stable, durable glucose control without the need for treatment intensification. Furthermore, each medication is associated with adverse effects, which range from hypoglycaemia to weight gain or bone loss. Unexpectedly, fibroblast growth factor 1 (FGF1) and its low mitogenic variants have emerged as potentially safe candidates for restoring euglycaemia, without causing overt adverse effects. In particular, a single peripheral injection of FGF1 can lower glucose to normal levels within hours, without the risk of hypoglycaemia. Similarly, a single intracerebroventricular injection of FGF1 can induce long-lasting remission of the diabetic phenotype. This Review discusses potential mechanisms by which centrally administered FGF1 improves central glucose-sensing and peripheral glucose uptake in a sustained manner. Specifically, we explore the potential crosstalk between FGF1 and glucose-sensing neuronal circuits, hypothalamic neural stem cells and synaptic plasticity. Finally, we highlight therapeutic considerations of FGF1 and compare its metabolic actions with FGF15 (rodents), FGF19 (humans) and FGF21.