Accurate measurement of circulating testosterone is critical in clinical practice because mismeasurement creates misdiagnosis and mismanagement. Over the last century, testosterone measurement has developed from nonspecific in vivo whole animal bioassays guiding its identification as the major mammalian androgen to highly sensitive modern in vitro cell-based androgen bioassays together with high throughput but inaccurate testosterone immunoassays and less available but accurate liquid and gas chromatography-mass spectrometry, the chemical reference methodologies. Although the sole unequivocal valid clinical indication for testosterone prescription is physiologic replacement therapy for pathologic hypogonadism, major off-label testosterone misuse abounds leading to a 100-fold increase in testosterone sales for prescribing has occurred over recent decades without any new approved indication. The pharmacological features of testosterone and its products as well as the basis for clinical management of testosterone replacement therapy are outlined, and approaches to avoiding or rectifying testosterone misuse are suggested.