Refractory periodontitis appears to be a patient phenomenon with a clinical pattern that may be the result of different influences including genetic factors and exogenous factors that alter the host response to the bacterial challenge. Different patients may have different mechanisms involved in their disease and therefore may show different response patterns following therapy. Although localized non-responsive sites in otherwise responsive patients should not be considered refractory periodontitis, such sites do present substantial therapeutic problems. Initial evidence suggests that local delivery tetracycline provides significant advantages in the management of such sites. Although refractory periodontitis cases appear to be primarily the result of host alterations, the most predictable approach to therapy at present involves systemic antibiotics in conjunction with local therapy. The goal of antibiotic therapy should be to eliminate from detection the target bacteria that were present prior to therapy. Good plaque control, regular professional maintenance therapy, regular microbial monitoring, and control of risk factors are important aspects of the long term maintenance of these cases.