There has been a dramatic evolution in both the clinical presentation and the methods used to diagnose pheochromocytoma and paraganglioma (PPGL) over the past nine decades. Due to the advances in biochemical testing and cross-sectional computed imaging, we have progressed from prior to 1970 when 90% of patients with PPGL were detected because of symptoms (paroxysms or hypertension) to 2018 when 60% of patients with PPGL are diagnosed due to an incidental discovery on cross-sectional imaging done for other reasons. Thus, the clinician should recognize the imaging phenotype typical for a pheochromocytoma. The differential diagnosis for those patients who present with symptoms spans the field of medicine. Biochemical case detection testing relies on measurement of fractionated metanephrines and catecholamines by tandem mass spectrometry or high-pressure liquid chromatography. The clinician should assess the relative likelihood of pheochromocytoma in each patient. Decisions for the type of test performed may be subject to clinical availability, cost, clinical experience of the ordering physician, and the local laboratory. However, it is key to understand the medications and clinical situations that may cause false-positive biochemical testing.