The biocompatibility of prosthetic mesh is dependent on a number of physicochemical properties that ultimately incite an optimal foreign body response. The magnitude and character of the foreign body response directly affect the clinical success of the hernia repair, with too little scar resulting in bulge or hernia recurrence and too much scar causing mesh wrinkling and pain. Moreover, it is important to consider the effect of a sustained foreign body response and scar remodeling on the combined strength of the mesh-tissue construct over time. Understanding key elements that determine the foreign body response, such as implant porosity, surface area, and filament size, is critical to the performance of surgery. New absorbable materials introduce the additional variable of durability and persistence of the foreign body response after the foreign body itself has dissolved. In this review, we discuss the experimental and clinical literature relating the quality of the foreign body response to the physical attributes of implants in an effort to demystify prosthetic mesh selection.