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In 1960, Robert James Gorlin and William Goltz, both American physicians, defined a new syndrome. Little did they realize that 40 years later, the pathways involved in its development would be provoking serious and sustained interest amongst a plethora of specialists. Fruit-fly biologists, oncologists, geneticists, dermatologists, indeed, hardly a medical or dental specialist gets excluded. To date, there have been some major breakthroughs in identifying abnormal gene sequences. Much has been discovered about this syndrome and its pivotal role in a number of cancer pathways but much more waits to be done or explained. This article sets out to discuss the current position and aims to stimulate further work on this intriguing and puzzling disorder.