The interplay of fluorination and structure of alkane self-assembled monolayers and how these affect hydrophobicity are explored via molecular dynamics simulations, contact angle goniometry, and surface-enhanced infrared absorption spectroscopy. Wetting coefficients are found to grow linearly in the monolayer density for both alkane and perfluoroalkane monolayers. The larger contact angles of monolayers of perfluorinated alkanes are shown to be primarily caused by their larger molecular volume, which leads to a larger nearest-neighbor grafting distance and smaller tilt angle. Increasing the Lennard-Jones force cutoff in simulations is found to increase hydrophilicity. Specifically, wetting coefficients scale like the inverse square of the cutoff, and when extrapolated to the infinite cutoff limit, they yield contact angles that compare favorably to experimental values. Nanoscale roughness is also found to reliably increase monolayer hydrophobicity, mostly via the reduction of the entropic part of the work of adhesion. Analysis of depletion lengths shows that droplets on nanorough surfaces partially penetrate the surface, intermediate between Wenzel and Cassie–Baxter states.