Downtown. Center City. The Central Business District. Whatever it is called, most American towns of any size and age have an area where most of the businesses were concentrated. Suburbanization, interstates, consolidation, and globalization have often take their tolls on such districts, but most towns continue to have such districts. Usually, such districts are reasonably central to the city. But not always.
Most of the exceptions are found where there is a terrain feature influencing development. Rivers, lakes, and seas can present a formidable obstacle or outright block to extending development in some directions. Hills, mountains, and valleys can have a similar influence. Sometimes even the angle of a slope itself can affect patterns of development.
Take the city of Cincinnati, Ohio for one example. Downtown is roughly centered with respect to east and west, but north and south is another matter entirely. The broad expanse of the Ohio River, beyond which lies the state of Kentucky, meant that any expansion southwards was not part of the city. And hills to the north of downtown were largely restricted to residential development. So downtown Cincinnati exists at the extreme southern edge of the city proper.
Toledo, Ohio is flatter than Cincinnati, but the obstacle presented by the width of the lower Maumee River slowed development to the east. Toledo's downtown is closer to centered than Cincinnati's, but it still isn't precisely balanced.
An extreme example of such a lack of balance in the position of a downtown can be found in the large village of Montpelier, Ohio. As a town of nearly five thousand, Montpelier has a nice little concentrated business district. Despite the relatively-flat terrain, this district is nevertheless located almost at the extreme northwest of the village's development. The vast majority of residential development extends south and east from the downtown. Why? I've got no clue, but it is a bit noticeable when looking at overhead imagery of the area.