If ion-channel proteins discretely encode temperature sensations (1,2), one would intuitively expect drug activation of cool and cold receptors (e.g. TRP (transient receptor potential)-M8, TRP-A1) to functionally suppress irritation, pain, and itch. Cold temperatures and menthol have some antipruritic activity, but for nasty itch, you want a drug that is more powerful. Icilin (Fig. 1) is qualitatively different from menthol in its pharmacology; hence, direct comparison of potency between the two is spurious (3–6). However, on common bioassay endpoints such as ‘wet-dog shake behavior’ (7) and calcium entry into cells expressing the cool receptor TRP-M8, icilin is 400–800 times more active than menthol. Icilin administered into the oral cavity produces sensations of cold in humans, but such sensations were not obtained when a 5% wt/vol solution in dimethylsulfoxide was applied to the forearm skin (7). Surprisingly, 2% icilin in Aquaphor® ointment was found to suppress pruritus when applied on the legs of a woman with xerosis, on the hands of a man with atopic dermatitis, on the anus of a man with hemorrhoids, and on the lips of a man with onset of cold sores. The icilin ointment had no odor or irritancy and its duration of action was 3–5 h. Such results motivated studies on the activity of icilin in an animal model of itching. Icilin. Synonyms: AG-3-5, 3,6-Dihydro-1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-2(1H)-pyrimidinone, 1-[2-hydroxy]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one. Weaned hairless rats maintained on a diet low in magnesium develop a transient erythematous maculopapulous rash with signs of generalized pruritus (8,9). The rats scratch and bite themselves leading to skin lesions (Fig. 2, left panel). Icilin, as a 2% powder suspended in Walgreens Advanced Care Lotion, applied once daily for 5 days significantly reduced bite and scratch marks in each animal (Fig. 2, right panel). Reduction in diseased animals was already observed after the first application and was overall 52% relative to vehicle-treated control animals (mean of 24 animals examined for 5 days in three independent studies). Worth mentioning, erythema was not inhibited and signs of pruritus returned upon cessation of treatment. The animals exhibited transiently ‘wet dog behavior’ after application of icilin at the tested concentration. Hairless hypomagnesemic rats on day 5 of treatment. Left panel: vehicle-treated animal with severe bite and scratch marks, taken as signs of generalized pruritus; right panel: animal treated topically once daily with 2% icilin lotion. Preliminary studies showed that the single oral median lethal dose of icilin in male and female mice and rats was 5–7 g/kg body weight, putting icilin into the category of a chemical with slight toxic potential for short-term effects (10). Purified icilin was not mutagenic in the Ames test system in strains TA 97, 98, 100, 102, 1535, 1537, 1538, with or without liver enzyme activation. Icilin is virtually water-insoluble; hence, administration of icilin onto the rectal mucosa of animals did not raise plasma levels above 1 µg/ml. Now the stage is set for the entrance of new players – clinical dermatologists – who must tell us if topical icilin or a related pyrimidine-2-one analog really manages to suppress that nasty itch.