This chapter explores spatial patterns and processes of residential segregation in St. Louis and Cincinnati using spatial analytical methods. Mapping Blacks by the location quotient and local Moran’s I shows that Blacks are more spatially clustered in St. Louis, and are more concentrated in Cincinnati. Spatial housing submarkets, local market segments with the distinct preference structure, are delineated using multivariate techniques; results demonstrate that St. Louis has more divided and polarized housing markets than Cincinnati. Spatially varying impacts of factors underlying housing market segmentation were examined using geographically weighted regression. It was shown that a premium for life cycle (or preference for family-oriented areas) is significantly high in few western suburbs of St. Louis whereas a high premium for job skills is pronounced in northern suburbs of Cincinnati. It appears that political fragmentation and topography is a culprit for unique market segmentation in St. Louis, and Cincinnati, respectively.