Microbial dental plaque is the initiator of periodontal disease but whether it affects a particular subject, what form the disease takes, and how it progresses, are all dependent on the host defenses to this challenge. Systemic factors modify all forms periodontitis principally through their effects on the normal immune and inflammatory defenses. Some good examples of this effect exist such as when there is a reduction in number or function of polymorphonuclear leukocytes (PMNs) that may result in an increased rate and severity of periodontal destruction. Many other systemic factors are much less clear cut and are difficult to causally link to periodontitis. In many cases the literature is insufficient to make definite statements on links between systemic factors and periodontitis. It is also at times difficult to be precise regarding the causative agent in systemic exposures such as smoking and even prescribed drug therapy. The possible role of systemic diseases and systemic exposures in initiating or modifying the progress of periodontal disease is clearly a complex issue. It is however generally agreed that several conditions may give rise to an increased prevalence, incidence, or severity of gingivitis and periodontitis. The categorization of the systemic modifying factors causing periodontitis and the evidence to support the role of these factors are the focus of this review. An attempt has been made to consider the conditions under broad headings, but it will be clear that many conditions fall within more than one category and that for several conditions only case reports exist whereas in other areas an extensive literature is present.