To review the optimal use of sensitive assays for thyroid-stimulating hormone (TSH) by clinicians.The available literature pertinent to the clinical application of sensitive TSH testing was identified through a systematic MEDLINE search and reviewed. Selection of materials for inclusion was based on clinical validity of the data and relevance to the study question.Sensitive TSH assays have contributed greatly to our basic knowledge of thyroid physiology and are a powerful clinical tool in the diagnosis and treatment of thyroid disease. The clinical applicability of these assays, as is our understanding of their appropriate use, is rapidly expanding. Based upon the best evidence and current understanding of thyroid physiology, strategies are presented for appropriate use of sensitive TSH assays in healthy outpatients, in patients who are likely to have a disturbed hypothalmic-pituitary-thyroid axis, and in patients on levothyroxane therapy.Although many clinical questions regarding the use of sensitive TSH assays remain to be studied, it has emerged as a powerful tool for the diagnosis and management of thyroid disease. Optimal use of sensitive TSH assays requires an understanding of TSH physiology and measurement, coupled with appropriate application and interpretation in specific clinical settings.