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Antibiotics have played a major role in the improvement of life expectancy in the last 50 years and have led many to believe that bacterial infections were about to vanish as a disease entity of any importance. Emerging problems resulting from a widespread use of antibiotics have modified the general perception of the capabilities of antimicrobial agents. Over the years, bacteria have become increasingly resistant to formerly potent antimicrobial agents, including some antiseptics. The use of antimicrobials may also disturb the delicate ecological equilibrium of the body, allowing the proliferation of resistant bacteria or non-bacterial micro-organisms. This shift may initiate new infections that are worse than the ones originally treated. No antimicrobial drug is absolutely non-toxic and the use of an agent carries accompanying risks. This paper discusses the development and occurrence of antimicrobial resistance in the subgingival flora towards antiseptics and local or systemic antibiotics and is focussed on the question: how can the outcome of periodontal therapy with/without antimicrobials be improved?