Phaeochromocytomas (PC) and paragangliomas (PGL) are tumours of neural crest origin that arise from the adrenal medulla or sympathetic and parasympathetic chain. Up to 15% of cases become metastatic which is difficult to predict and cure, hence individuals with metastatic disease have a poor prognosis. More than a third of PCs and PGLs are associated with germline variants in a growing list of susceptibility genes. A high rate of heritability without reliable biomarkers, understanding of metastatic potential burdens patients, carriers, and the healthcare systems. Identifying and understanding pathogenic mechanisms associated with gene variants found in patients would therefore improve disease-risk estimates for efficient clinical management and uncover potential therapeutic targets. The primary aim of this thesis was to characterise different gene variants associated with PC/PGL by determining distinct functional outcomes in vitro and ex vivo. Firstly, in vitro assay was developed to demonstrate distinct impairment in protein function stemming from different pathogenic germline SDHB variants affecting protein localisation, SDH activity and interaction with the other subunit of the SDH enzyme. Also, functional study of additional SDHAF3 and EPAS1 variants uncovered interaction sites with SDHB and potential disease modifying outcomes respectively. Secondly, the utility of mass-spectrometry based measurement in determining biochemical imbalance arising from SDH and FH deficiency was demonstrated ex vivo using archival FFPE tumour sections. Lastly, functional study of two novel germline MAX variants was conducted to determine their pathogenic potential through impaired nuclear localisation and regulation of oncogenic transcriptional activity. Together, the work described in this thesis may contribute to improved clinical algorithms, early detection and management of patients by providing evidence for disease-risk predictions.