The pancreas is innervated by sensory neurons originating from the vagus and the spinal nerves. A large proportion of these sensory neurons express the transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel. Karam et al. used a combination of chemical and surgical models to address whether TRPV1 sensory neurons directly modulate functional β-cell mass and consequently alter glucose homeostasis. Their data suggest that TRPV1 sensory neurons directly modulate, at least in part, pancreatic β-cell function in a sex-dependent manner.