This paper investigates the formation of employment sub-centers from a new perspective of heterogeneity in agglomeration economies. Using highly granular commercial and residential land-use data (2001–2011) in Chicago, we measure how the locations of jobs, population, quality-of-life amenities, and transportation networks shape specific and heterogenous sub-centers. First, the results suggest that the CBD as it was traditionally defined is no longer the primary source of agglomeration externalities for the new economic sectors; sub-centers with sector-specific positive agglomeration externalities have stronger correlations with new commercial establishments. Secondly, residents appear to give the highest weight to quality-of-life amenities in choosing where to live. Both trends imply dis-incentives for CBD agglomeration. These findings connect the heterogeneous production theories with land use planning and urban design, through new empirical insights into how urban sub-centers grow. Furthermore, we put forward a method for forecasting of future sub-center growth through measuring changes in the probability of commercial development, and discuss its practical implications for planning and design in Chicago.