The biologic behavior of a facial filler determines its advantages and disadvantages. The purpose of this article is to look at the relevant biology as part of a logical basis for making treatment decisions. Historical perspectives and biologic characteristics such as local tissue reaction (including phagocytosis and granulomatous inflammation) cross-linking, particle concentration, immunogenicity, biofilm formation, gel hardness, and collagen neogenesis are considered. Bovine collagen is the most immunogenic facial filler. Porcine and bioengineered human collagen implants have very low immunogenicity, but allergic reactions and elevations of IgG are possible. Cross-linking and concentration affect the longevity of collagen and hyaluronic acid fillers. Gel hardness affects how a hyaluronic acid filler flows through the syringe and needle. Calcium hydroxylapatite, poly-L-lactic acid, and polymethylmethacrylate fillers have been shown to stimulate collagen neogenesis. It appears that any facial filler can form a granuloma. Bacterial biofilms may play a role in the activation of quiescent granulomas. Various authors interpret the definition and significance of a granuloma differently.