River systems have been the home to many civilizations (Nile, Indus, Tigris and Euphrates) but how come one did not develop along the Mississippi?
A few people here have already provided links to information on the Mississippians, but I thought I'd give a brief overview here. I worked for a year and a half as an archaeologist in East St. Louis, excavating a nearby town to Cahokia. I was less than a mile from the river, and could see the Gateway Arch in St. Louis from where I was digging.
We call this culture the Mississippians, because the largest city, Cahokia, was on the Mississippi river (it's about 20 minutes east of St. Louis, and I highly recommend visiting the state park and museum if you're ever in St. Louis). But there were Mississippian towns as far north as Wisconsin and as far south as Louisiana, and from Oklahoma to Georgia. Mostly they popped up along the major rivers, the Mississippi and the Ohio. Unlike the Aztecs, these was chiefdoms, not a state. That means that, while there were a lot of cultural similarities, these cities and towns were never unified. Based on the spread of languages in historic times (the last 500 years) we can be fairly certain that these people didn't even all speak the same language, or even related languages. So why do we consider them one culture known as the Mississippians? Well, here's what they have in common:
They grew corn and beans to feed their cities (both of those plants were domesticated in Mexico, btw, and spread north). This wasn't their only source of food, they did hunt deer and birds and fish, and grew other supplemental crops, but corn especially and beans were central to their agriculture.
They built mounds. These mounds were generally for ceremonial purposes. Some were burial mounds (like Mound 72 at Cahokia), some were charnel houses, some held council houses for large group meetings, and some, like Monks Mound at Cahokia, held houses of important people. These were built by carrying baskets of dirt by the thousands, and then covering them in clay. Monks Mound, where the chief-priest of Cahokia lived, was at the north end of the central plaza, and is has a larger base than the Great Pyramid at Giza, to give you a sense of scale.
Their iconography is all fairly similar. They worshiped the "Long-Nosed God" who bears a strong resemblance to Red Horn of Siouan legend, which in turn has some strong parallels to the legend of the Hero Twins of the Aztecs and other Mesoamerican cultures. They worshiped the sun, including using a woodhenge in Cahokia (which has been reconstructed for the state park) to mark the solstices and equinoxes.
Cahokia itself, though it was roughly the same size as London in 1100 (10-15k people is the best guess, though I've seen as high as 35k for the greater Cahokia area) was effectively abandoned by about 1275, it appears. That can't be blamed on European diseases, so it was more likely economic problems. Many other Mississippian sites did last longer, including Moundville in Alabama and Shiloh in Tennessee (which is actually a National Park, because the famous Civil War battle happened there), but even they were gone before Columbus, much less De Soto. But De Soto does talk about fortified towns in the Southeast that bear strong resemblances to Mississippian towns, so it's thought that these small towns were what was left of the Mississippians at the time. But De Soto's men were the ones who carried European diseases to America and Canada, and so they were probably the last Europeans to see any Mississippian peoples, as their lifeways were so altered by contact and disease.
Others have discussed Cahokia, and I'll probably add a bit more on that front in replies to those comments. Here, though, I wanted to discuss what came before Cahokia.
Between 2200BCE and 700BCE, the lower Mississippi was home to the Poverty Point Culture, flanking the Mississippi River in both eastern Louisiana and western Mississippi (map. People began construction of the major features of the Poverty Point site itself around 1650 BCE. It's a massive earthworks project, composed of concentric rings over half a mile (about 1.2km) in diameter and several earthen pyramids. The largest of these, the Bird Mound, is twice the size and a few centuries older than the Olmec's Great Pyramid of La Venta, the most famous of the early Mesoamerican pyramids. Among the largest earthen pyramids of North America, it's in competition for second place along with the later Mississippian-era Emerald Mound (Cahokia's Monks Mound has a firm grasp on first place).
The current dominant interpretation of the site is that the rings were the foundations of of homes that populated the core of the settlement, based on what little evidence of postmolds has survived centuries of erosion and decades of plowing before archaeologists first began to study the site. If so, it would be the earliest example of such a large-scale settlement in North America and would have been home to several thousand people including homes built outside the core area of the settlement. Poverty Point achieved this population without the benefit of maize-based agriculture that fueled the development of Mesoamerican and Mississippian cultures. In fact, it seems to have done so without agriculture at all. The culture seems to have fed itself primarily from the rivers and bayous, with fish being the most prevalent food source.
Given its size and the concentration of trade items at the site and, to a slightly lesser extent, at smaller Poverty Point sites in its vicinity (within about 20 miles), the Poverty Point site seems to have been the de facto "capital" of the culture, influencing the region through trade and culture if not through political ties as well. Poverty Point's trade contacts stretched far to the north, reaching up the Mississippi to the copper-producing regions around Lake Superior.
The Poverty Point Culture inherited some of its characteristics from earlier cultures (such as the builders of Watson Brake nearly 2000 years before construction began at Poverty Point and about whom little is known) and passed on some of the characteristics, through intervening societies like the Hopewell, to the Mississippians. As much as Cahokia tends to dominant these sorts of conversations, it's important to remember that it didn't spring up out of nothing.
I read a good book a few years back about Cahokia, a civilization along the Mississippi in Missouri near where St. Louis is now.
Updated to not use Amazon link.