I am thinking about destroying Italy.
Not literally, but in terms of my basic Mediterranean geography. Let's say, for example, that the Vesuvius eruption in 79 AD didn't just bury Pompeii. Let's say it was cataclysmic in nature, blowing off the bottom of Italy's boot and turning most of the peninsula into islands. The southern-most of these islands are still, hundreds (thousands?!) of years later, within an active volcanic zone. Shrouded in mist and smoke, and inimical to navigation, these islands have become a haven for not only strange beasts, but also for those who seek to hide from the region's powers -- pirates and criminals. Few dare the Straits of Fire.
The explosion ended the reign of a powerful and dominant Empire, whose culture, architecture, and language still pervade throughout the region.
It also caused religious upheaval. The ash that blotted out the sky lasted for years, not only obliterating the Empire's native religion, but giving rise to various Sky Cults. Three of those cults grew into the dominant religions of the present -- the Sun, the Moon, and the Stars.
The north literally fractured into island city-states. Over time, they grew into dominant cultural, political, and social forces in the region. Many ships headed East-West travel through these islands to avoid the Straits of Fire. Tariffs, trade, and smuggling have enriched these states significantly.
Of course, all of this makes my "just use the map of the Mediterranean" idea only somewhat worthwhile, but I think this significant geological event is just the thing to get me going on many of the ideas I have for the setting.