Pheochromocytomas are chromaffin cell tumors, mostly originating from the adrenal medulla, and represent a rare cause of hypertensiondue to excessive production of catecholamines (norepinephrine and/or epinephrine). More than 10% occur in families with multiple endocrine neoplasia type II, von Hippel-Lindau disease, neurofibromatosis type I, and familial carotid body tumors. Since approximately half of the afflicted patients present without or with only episodic hypertension, detailed clinical evaluation and sensitive biochemical tests are mandatory for the diagnosis, which relies on the detection of increased catecholamine production. Commonly employed tests such as the measurement of free catecholamines in plasma and urine or of their metabolites, vanillylmandelic acid and total metanephrines (= free + conjugated normetanephrine and metanephrine) in urine, suffer from interference from external factors and sometimes low clinical sensitivity and/or specificity. Recent technical advances now allow us to measure plasma free (unconjugated) metanephrines, thus increasing clinical sensitivity and specificity to close to 100%. Plasma free metanephrines offer the following advantages for the detection of pheochromocytomas: (i) independence of short-term changes in catecholamine secretion which may result from change of posture, exercise or intraoperative stress, (ii) information on long-term increase of catecholamine production, (iii) tight correlation with tumor mass, and (iv) only minor interference from drugs. This method does not need time-consuming standardized procedures for blood sampling, which are a prerequisite for the determination of free catecholamines. In conclusion, it is therefore recommended to use plasma free metanephrines--after meticulous clinical screening--as the first-line biochemical test for detecting pheochromocytomas.