A multifaceted antimicrobial approach is necessary for the successful management of destructive periodontal disease. Effective antimicrobial periodontal therapy aims to overwhelm periodontal pathogens with aggressive initial therapy and prevent previously suppressed pathogens from rising up anew through daily oral hygiene measures and frequent professional cleaning. Current antimicrobial periodontal therapy employs mechanical debridement performed with and without surgery, antibiotics, and antiseptics. Subgingival irrigation with povidone-iodine at the dentist's office and subgingival irrigation with dilute sodium hypochlorite for home-care constitute effective, safe, and affordable periodontal antimicrobial therapy. This article describes theoretical and practical guidelines for implementing rational and cost-effective antimicrobial principles in the management of periodontal disease.