Methods for combinatorially processing semiconductor substrates are provided. The methods may involve receiving a substrate into a combinatorial processing chamber and sealing a plurality of flow cells against a surface of the substrate. The plurality of flow cells is enclosed within the combinatorial processing chamber to define an enclosed external environment for the plurality of flow cells. A pressure differential is created between a reaction area of the plurality of flow cells of the combinatorial processing chamber and the external environment, wherein each flow cells of the plurality of flow cells defines a site isolating region of the substrate. The regions the substrate are then combinatorially processed.