I was thinking about cities where the downtown area is not in the geographic center of the region. There's a number of factors why it might not be there; natural features, political boundaries, and so on.
Some cities have such a large critical mass that the location of the CBD really isn't a factor - see Chicago, San Francisco or Seattle, for instance. What about more "normal" cities, though? Do you think that, among cities of an equivalent size and economic health, off-center downtowns are at a disadvantage compared to those with more "centered" downtowns?
Some examples ...
Indianapolis - centerered downtown
Denver - geographically centered downtown, development in northeast burbs a bit stifled
Columbus - centered downtown
Buffalo - offset downtown (Niagara River/Lake Erie/Canada to west, stunted development in Southtowns/snow belt compared to booming Northtowns)
Cleveland - offset downtown (Lake Erie to north, all development south of city center)
St. Louis - offset downtown (dominant growth pattern to west and northwest, Mississippi River and lightly populated Illinois side to east)
Atlanta - offset downtown (dominant growth pattern to north, perception of Ponce de Leon as a cultural boundary)
Johannesburg - offset downtown (most "formal" development to north and east of city center)