Glucose-inhibited neurones are an integral part of neurocircuits regulating cognitive arousal, body weight and vital adaptive behaviours. Their firing is directly suppressed by extracellular glucose through poorly understood signalling cascades culminating in opening of post-synaptic K(+) or possibly Cl(-) channels. In mammalian brains, two groups of glucose-inhibited neurones are best understood at present: neurones of the hypothalamic arcuate nucleus (ARC) that express peptide transmitters NPY and agouti-related peptide (AgRP) and neurones of the lateral hypothalamus (LH) that express peptide transmitters orexins/hypocretins. This talk will predominately focus on the effects of glucose on orexin neurons, which are inhibited by glucose due to activation of postsynaptic K currents. Glucose-induced hyperpolarization and inhibition are unaffected by glucokinase inhibitors such as alloxan, D-glucosamine, and N-acetyl-D-glucosamine, and mimicked by the non-metabolizable glucose analogue 2-deoxyglucose, but not by stimulating intracellular ATP production with lactate. This hints to a “non-metabolic” signal strategy in orexin neurons [1,2]. A distinct group of orexin neurons exhibits only transient inhibitory responses to sustained rises in sugar levels, a sensing strategy involves time-dependent recovery from inhibition via adaptive closure of leak-like K(+) channels. Combining transient and sustained glucosensing allows orexin cell firing to maintain sensitivity to small fluctuations in glucose levels while simultaneously encoding a large range of baseline glucose concentrations [3].