Cypermethrin is a neurotoxic pyrethroid insecticide, which following iv administration to rats at 25 mg/kg, produces a reproducible sequence of signs of toxicity. These include progressively: chewing, salivation (mean time, 11 min), clonic convulsions (mean time, 27 min), and sinuous writhing movements (mean time, 42 min). Animals were killed at these defined stages of toxicity and the concentration of cerebellar amino acids and cyclic nucleotides determined. Cypermethrin increased cerebellar cyclic GMP at the earliest time measured (salivation), without changing cyclic AMP. Pretreatment of animals with atropine blocked the salivation, but did not appear to alter the increase in cerebellar cyclic GMP. Blood glucose and lactate were elevated at all times examined, while plasma ammonia was elevated at onset of the first convulsion. A corresponding increase was seen in glucose, lactate, and ammonia in the cerebellum. No significant changes were observed in the concentration of cerebellar glutamate, glutamine, γ-aminobutyrate, creatine phosphate, or ATP. No increase in cyclic GMP was seen when slices of cerebellum were incubated with cypermethrin in vitro. The earliest biochemical change observed following cypermethrin administration was an increase in cerebellar cyclic GMP, which did not appear to be related to either the convulsive state of the animal or to muscarinic cholinergic stimulation. Studies in vitro with slices of cerebellum suggest that the stimulus for elevating cyclic GMP may occur outside the cerebellum.