BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are potentially lethal yet usually surgically curable causes of endocrine hypertension; therefore, once clinical suspicion is aroused it is imperative that clinicians choose the most appropriate laboratory tests to identify the tumors. CONTENT: Compelling evidence now indicates that initial screening for PPGLs should include measurements of plasma free metanephrines or urine fractionated metanephrines. LC-MS/MS offers numerous advantages over other analytical methods and is the method of choice when measurements include methoxytyramine, the O-methylated metabolite of dopamine. The plasma test offers advantages over the urine test, although it is rarely implemented correctly, rendering the urine test preferable for mainstream use. To ensure optimum diagnostic sensitivity for the plasma test, reference intervals must be established for blood samples collected after 30 min of supine rest and after an overnight fast when measurements include methoxytyramine. Similarly collected blood samples during screening, together with use of age-adjusted reference intervals, further minimize false-positive results. Extents and patterns of increases in plasma normetanephrine, metanephrine, and methoxytyramine can additionally help predict size and adrenal vs extraadrenal locations of tumors, as well as presence of metastases and underlying germline mutations of tumor susceptibility genes. SUMMARY: Carried out correctly at specialist endocrine centers, collection of blood for measurements of plasma normetanephrine, metanephrine, and methoxytyramine not only provides high accuracy for diagnosis of PPGLs, but can also guide clinical decision-making about follow-up imaging strategies, genetic testing, and therapeutic options. At other centers, measurements of urine fractionated metanephrines will identify most PPGLs.