Until recently, it was widely accepted that bacteria participate in caries pathogenesis mainly through carbohydrate fermentation and acid production, which promote the dissolution of tooth components. Neutrophils, on the other hand, were considered white blood cells with no role in caries pathogenesis. Nevertheless, current literature suggests that both bacteria and neutrophils, among other factors, possess direct degradative activity towards both dentinal collagen type-1 and/or methacrylate resin-based restoratives and adhesives, the most common dental restoratives. Neutrophils are abundant leukocytes in the gingival sulcus, where they can readily reach adjacent tooth roots or gingival and cervical restorations and execute their degradative activity. In this review, we present the latest literature evidence for bacterial, dentinal, salivary, and neutrophil degradative action that may induce primary caries, secondary caries, and restoration failure.