Recent advances indicate that periodontitis is driven by reciprocally reinforced interactions between a dysbiotic microbiome and dysregulated inflammation. Inflammation is not only a consequence of dysbiosis but, via mediating tissue dysfunction and damage, fuels further growth of selectively dysbiotic communities of bacteria (inflammophiles), thereby generating a self-sustained feed-forward loop that perpetuates the disease. These considerations provide a strong rationale for developing adjunctive host-modulation therapies for the treatment of periodontitis. Such host-modulation approaches aim to inhibit harmful inflammation and promote its resolution or to interfere directly with downstream effectors of connective tissue and bone destruction. This paper reviews diverse strategies targeted to modulate the host periodontal response and discusses their mechanisms of action, perceived safety, and potential for clinical application.