Spicy food does not only provide an important hedonic input in daily life, but has also been anedoctically associated to beneficial effects on our health. In this context, the discovery of chemesthetic trigeminal receptors and their spicy ligands has provided the mechanistic basis and the pharmacological means to investigate this enticing possibility. This review discusses in molecular terms the connection between the neurophysiology of pungent spices and the "systemic" effects associated to their trigeminality. It commences with a cultural and historical overview on the Western fascination for spices, and, after analysing in detail the mechanisms underlying the trigeminality of food, the main dietary players from the transient receptor potential (TRP) family of cation channels are introduced, also discussing the "alien" distribution of taste receptors outside the oro-pharingeal cavity. The modulation of TRPV1 and TRPA1 by spices is next described, discussing how spicy sensations can be turned into hedonic pungency, and analyzing the mechanistic bases for the health benefits that have been associated to the consumption of spices. These include, in addition to a beneficial modulation of gastro-intestinal and cardio-vascular function, slimming, the optimization of skeletal muscle performance, the reduction of chronic inflammation, and the prevention of metabolic syndrome and diabetes. We conclude by reviewing the role of electrophilic spice constituents on cancer prevention in the light of their action on pro-inflammatory and pro-cancerogenic nuclear factors like NFκB, and on their interaction with the electrophile sensor protein Keap1 and the ensuing Nrf2-mediated transcriptional activity. Spicy compounds have a complex polypharmacology, and just like any other bioactive agent, show a balance of beneficial and bad actions. However, at least for moderate consumption, the balance seems definitely in favour of the positive side, suggesting that a spicy diet, a caveman-era technology, could be seriously considered in addition to caloric control and exercise as a measurement to prevent and control many chronic diseases associate to malnutrition from a Western diet.