Invadopodia are subcellular protrusive structures associated with sites of extracellular matrix (ECM) degradation. Little is known about the regulation of invadopodia functions by ECM properties. I will discuss a joint experimental-computational study in which we have modeled and tested the regulation of invadopodia formation and function by crosslinked gelatin and collagen substrates. We find that crosslinking inhibits degradation and penetration of invadopodia in dense substrates, such as gelatin, but not in loose collagen matrices. These results provide a framework for consideration of diverse types of matrices that invasive cells may experience in vivo.