Find a grave link.
A skull as such doesn't make such a great Call of Cthulhu artefact, as it is human in origin, not mythos related. It would make a great item to be used in Unknown Armies.
Of course, in a Call of Cthulhu game, it may be on show, labelled as Montcalm's skull, but the cultists know, or at least believe it to actually be the skull of a great shaman and cult leader. The skull itself may not actually have power, but the possession of it can be used as an identifier, or bargaining tool with a being of power, thereby allowing the cult access to something they do not yet have.
The investigators could be hired to find the stolen skull, and thereby are in a race against time to find it before the cult accesses what it wants. Otherwise, the cult succeeds in it's plan, unleashing horrors in their quest for power that the Investigators must then defeat. Recovering/destroying the skull thereby ending the threat to the city.
In a modern game, of course, the skull is no longer on display, but since its burial place is known, that shouldn't stop anyone!