There have been increasing numbers of applications using oral fluids, saliva in particular, as the target substrate for performing clinical diagnostic tests. These have focused primarily on point-of-care (POC) testing. These POC testing approaches range from, for example, currently available, highly specialized screening tests for the presence of antibodies recognizing HIV to the potential development of “lab-on-a-chip” platforms. Broad claims have been made that the latter will revolutionize clinical laboratory testing. From the perspective of large centralized clinical laboratories, multiple issues must be considered before implementing individual tests using saliva as the target fluid in a POC format or using saliva as a universal test fluid for measuring multiple analytes in a centralized laboratory format. The current scope of laboratory testing is large and comprehensive, involving both POC and centralized testing. Current academic laboratory programs have the ability to qualitatively identify and/or quantitatively measure several thousand analytes in various target matrices including blood, plasma, serum, urine, joint fluid, pleural fluid, peritoneal fluid, cerebrospinal fluid, and tissue. These tests fall into multiple clinical pathology disciplines, including clinical chemistry, hematology, coagulation, transfusion medicine, microbiology, cytogenetics, molecular diagnosis, and immunology. In addition, before implementing a given test, multiple issues need to be evaluated to ensure the validity of the reported result; these include considerations involving the three major phases of testing: preanalytical (e.g., patient identification and specimen collection, stability, and transport), analytical (e.g., sensitivity, specificity, accuracy, and precision), and postanalytical (e.g., reporting results, quality improvement, and turn-around-time).