BACKGROUND: Conventional periodontal treatment, performed quadrant by quadrant in multiple visits, was re-evaluated in the early 1990s when the full-mouth disinfection concept was introduced. Over the years, several modifications to the full-mouth disinfection approach have been suggested. OBJECTIVE: The purpose of this article is to review the evolution of full-mouth disinfection during the past 20 years, to specify its indications and to consider the prospects for this approach. MATERIALS AND METHODS: An electronic and manual search of the literature, ending in December 2016, was performed by two independent researchers. Only pivotal studies and randomized controlled clinical trials published in the English language that evaluated a new approach to full-mouth disinfection were selected. RESULTS: According to the studies included in our analysis (21 articles), several modified full-mouth disinfection protocols have been designed including: full-mouth treatment without chlorhexidine, the extension of hygiene methods and an increase in the duration of post-treatment chlorhexidine use, the replacement of chlorhexidine with other antiseptics, supplementation with antibiotics or probiotics, full-mouth antimicrobial photodynamic therapy and one-stage full-mouth disinfection combined with a periodontal dressing. CONCLUSION: Since 1995, several modifications have been suggested to improve the effectiveness of full-mouth disinfection. The majority of the studies demonstrate that the results obtained with full-mouth disinfection and its variants are equivalent to each other and to those obtained with the conventional quadrant method. Currently, the selection of this technique remains empirical and depends on the preferences of the practitioner and the patient. In the future, a patient-centered approach should be the best indication for the use of this technique.