I've always been fascinated by the story of Cairo, Illinois. It's at the confluence of the Mississippi and Ohio Rivers. It seems that all of the ingredients were there for it to develop into a major city that would eventually anchor a tri-state metropolitan area. But it didn't.
Today, the city where Mississippi and Ohio meets have a population of roughly 3,000 people. I know that Cairo has a history of racial tension but that arose after the city SHOULD have already been established as a major city.
What happened? It just seems weird that the Ohio and Mississippi meet in what is essentially the middle of nowhere.
Cairo is extremely flood-prone, completely surrounded by levees. Its situation certainly did not attract early settlers: it wasn't even founded until 1837, decades after other areas of Southern Illinois and the Ohio Valley, and grew very slowly.
Merely being at a confluence of rivers that can handle the same kind of boats is not a great advantage over other river ports. Any cargo just sails past. As a port, having easily accessible bluffs out of danger in spring floods would give places like St. Louis the advantage. Places where cargo must be shifted from ship to barge or railroad (like Chicago) are classic entrepôts, and have natural advantages as places to set up factories. Once the Illinois Central Railroad bridged the Ohio, it could transport agricultural products all the way to New Orleans with no need to transfer cargos to riverboats at Cairo.