Glucose meters, used for self-monitoring and in a myriad of healthcare settings, provide for frequent and rapid measurement of glucose levels using a capillary fingerstick blood sample. However, due to their limitations, self-monitoring glucose meters based on strip technology were never intended for use in acute care settings. Hematocrit, oxygen therapy, drugs, and metabolites can falsely increase or decrease glucose test results in hospitalized patients. Problems observed during the use of glucose meters in critically ill patients has raised awareness of their safety for professional use in hospitalized patients. Hospital laboratories should note the limitations of their glucose meter methodology and recognize conditions for intended and off-label use of the test system. Originally, all glucose meters were cleared as over-the-counter (OTC) products. By definition, the OTC labeling made these devices waived for use in hospitals based on the Clinical Laboratory Improvement Amendments of 1988 (CLIA). In the United States, off-label use of glucose meters changes the meter classification from CLIA-waived to CLIA high complexity. This shift to high complexity classification may limit the staff who can perform testing and necessitates additional resources to meet CLIA compliance. These consequences must be considered for glucose meter testing in the critically ill and for other patient conditions for which the manufacturer may not have thoroughly evaluated the analytical performance of a meter in all patient care settings. This white paper explores the limitations of strip-based glucose meters, distinguishes between intended and off-label use, and identifies the consequences of using a glucose meter outside of the manufacturer package insert recommendations, including the actions required to meet CLIA high complexity requirements. This white paper does not define “critically ill,” but provides readers with the factors to consider in developing their own definition of “critically ill.” The contents of this white paper represent the opinions of CLSI volunteers, and each organization using blood glucose meters should determine whether it is practicing off-label use and collaborate with its internal quality and regulatory departments to develop an appropriate plan to manage this off-label use. Alternatively, organizations should be advised to review their management plan with the Centers for Medicare & Medicaid Services and US Food and Drug Administration (FDA) representatives, if necessary.