Periodontitis is an inflammatory condition of the periodontium that leads to destruction of the supporting structures of the tooth, including loss of attachment and alveolar bone. A clinician’s first line of treatment for periodontitis is traditionally mechanical periodontal therapy, including oral hygiene instructions together with scaling and root planing. However, it has been shown that mechanical therapy may not always be effective in halting disease. Adjunctive chemotherapeutics, such as systemic antibiotics or host-modulating agents, may improve the treatment outcome of periodontitis. Using relevant terms such as “adjunctive antibiotics” and “systemic chemotherapeutics” in a manual search of the PubMed database, the authors have prepared a narrative review of the chemotherapeutics currently used in the field. Results of the search and review show that adjunctive antibiotics may be useful in cases of aggressive periodontitis, refractory periodontitis, and in some patients who are immunocompromised, such as heavy smokers or poorly controlled diabetics. Host-modulating agents are generally recommended only as the last resort and are limited to the use of submicrobial dose doxycycline. Microbial testing may be indicated, particularly in aggressive periodontitis cases or refractory cases. Using these results, a decision tree is provided for clinicians to determine when adjunctive chemotherapeutics may be indicated.