We have prepared 3D superhydrophobic materials from biocompatible building blocks, where air acts as a barrier component in a porous electrospun mesh to control the rate at which drug is released. Specifically, we fabricated poly(epsilon-caprolactone) electrospun meshes containing poly(glycerol monostearate-co-epsilon-caprolactone) as a hydrophobic polymer dopant, which results in meshes with a high apparent contact angle. We demonstrate that the apparent contact angle of these meshes dictates the rate at which water penetrates into the porous network and displaces entrapped air. The addition of a model bioactive agent (SN-38) showed a release rate with a striking dependence on the apparent contact angle that can be explained by this displacement of air within the electrospun meshes. We further show that porous electrospun meshes with higher surface area can be prepared that release more slowly than control nonporous constructs. Finally, the entrapped air layer within superhydrophobic meshes is shown to be robust in the presence of serum, as drug-loaded meshes were efficacious against cancer cells in vitro for >60 days, thus demonstrating their applicability for long-term drug delivery.