Which river valley inside the present-day united states was the site of significant european settlement prior to 1750?

The Mississippi Valley was very attractive for early colonizers. The Spaniards first went there in 1541, hoping they would find gold just like their fellow citizens had done in Mexico two decades earlier. But their venture didn't bear any fruit. Then, in 1673, French came to explore the land. Soon enough, missionaries followed their steps, and the first small settlements were formed, in spite of many troubles (such as outbreaks of smallpox).