Gingival crevicular fluid (GCF), a serum transudate or inflammatory exudate, can be collected from the gingival crevice surrounding the teeth. As such, the fluid reflects the constituents of serum, the cellular response in the periodontium, and contributions from the gingival crevice. The study of GCF has focused on defining the pathophysiology of periodontal disease, and identification of a potential diagnostic test for active periodontitis. The majority of markers that have been identified as potential candidates for such a test are measures of inflammation (i.e., prostaglandin E2 (PGE2), neutrophil elastase, and the lysosomal enzyme beta-glucuronidase). Further, analysis of inflammatory markers in GCF may assist in defining how certain systemic disorders (e.g., diabetes mellitus) can modify periodontal disease, and how periodontal disease/periodontal inflammation can influence certain systemic disorders (i.e., cardiovascular/cerebrovascular diseases). Methodological concerns related to the collection and analysis of GCF are important factors that need to be considered when studying GCF. Practical concerns argue against the widespread clinical application of GCF as an adjunct to periodontal diagnosis. Rather, analysis of GCF-derived mediators in saliva may serve as a means of rapid screening for periodontal disease.