Opportunities for synthetically controlling the molecular architecture of catalytic active sites supported on amorphous silica versus zeolitic silicates are critically examined, and the role that support crystallinity could play on catalytic properties is assessed. We first summarize structural features of active sites on silicate supports and contrast the inherent disorder of amorphous silica surfaces to the order of crystalline zeotypes. We then analyze, within the context of selected catalytic systems currently employed in industrial practice, how these structures affect inner- and outer-sphere environments of isolated active sites, and how these environments could impact catalytic activity and the development of next generation catalysts.