We investigate the creation of large area mesoscale structures by controlling the dewetting pathways of thin polymer films on physically heterogeneous substrates comprising a two-dimensional (2-D) array of square pillars. Depending on the initial configuration and thickness of the film, dewetting produces a variety of both ordered and disordered structures. The substrate pattern strongly influences the dewetting pathways as well as the organization and size of the polymer structures. The key findings are: (i) the lateral confinement imposed by the substrate pattern can reduce the length-scale of the dewetted structure by one to two orders of magnitude as compared to dewetting on the same homogeneous substrate. (ii) When the polymer film is thin (<40 nm) and placed in a conformal contact with the patterned substrate, a perfect array of droplets occupying the interstitial spaces of pillar patterns is formed within a narrow range of film thickness. Nonlinear simulations show similar behavior. (iii) In contrast, for a flat polymer film resting only on the pillars and hanging freely over the channels, the dewetted droplets assemble on top of the pillars. (iv) For thicker films (>40 nm), dewetting progresses by nucleation of large holes, uncorrelated to the substrate pattern. The dewetted pattern in this case forms on multiple length-scales consisting of ∼10 μm droplets resulting from the coalescence of the holes and small (<1 μm) droplets at the interstitial locations due to stick–slip of the retracting contact line.