The integrity of specimens submitted to the clinical laboratory for analysis is a major determinant of the accuracy with which the analyte can be measured, and the subsequent clinical utility of the test result. There are a wide variety of preanalytical factors that can adversely impact the integrity of specimens that are submitted for analysis. The most common preanalytic factor affecting the acceptability of specimens for analysis is the presence of endogenous interfering substances. Endogenous interferences most commonly encountered in the clinical laboratory include the presence of high plasma hemoglobin concentrations, visible turbidity due to the presence of high concentrations of triglycerides, and interference due to high concentrations of bilirubin. Hemolysis, lipemia and icterus can present significant challenges to laboratorians, especially when specimens contain multiple different interfering substances simultaneously. In addition, endogenous interferences may occur only when the analyte that is being measured is at a certain concentration within the specimen. Laboratorians must be familiar with the limitations imposed by endogenous interfering substances and understand their impact on the clinical utility of laboratory tests.