The laboratory workup of patients with phaeochromocytoma and extra-adrenal paraganglioma (PPGLs) has traditionally focussed on biochemical measurements of tumour secretory products or their metabolites. To first think of the tumour remains the critical step for screening patients with signs and symptoms of catecholamine excess. For such cases biochemical testing is usually straightforward and should always include measurements of plasma free or urinary fractionated metanephrines. Mass spectrometric-based methods show numerous advantages over other methods of measurement. Preanalytical factors that can impact test results and use of appropriate reference intervals represent other important considerations to reduce false-positive test results without negatively impacting tumour detection. While such considerations are of general importance for all patients with suspected PPGLs, the need to distinguish potentially metastatic from benign tumours has stimulated searches for additional means to stratify patients according to metastatic risk. Increasing recognition of the heterogeneity of PPGLs related to driver-mutations of numerous tumour susceptibility genes adds further to the complexity of case detection and patient management. PPGLs can no longer be regarded as a uniform tumour entity, but rather as a highly heterogeneous group of chromaffin cell neoplasms with different ages of onset, secretory profiles, locations and potentials for malignancy according to underlying genetic mutations; all are factors that impact biochemical test results. Large tumour size, extra-adrenal location, immature phenotypic features and presence of succinate dehydrogenase type B mutations for example are all inter-related risk factors for malignancy that can be identified by extents and patterns of increases in biochemical test results. Such patterns thereby provide important clues when PPGLs are first diagnosed for consideration of the most likely underlying genetic cause and optimising management of individual patients. Patients with identified mutations of specific genes require a personalized approach to management that can include different strategies for biochemical testing, tumour localization, and potentially, therapeutic interventions.